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` Treatment Options for Insomnia
`
`A more recent article on insomnia is available. (https://www.aafp.org/afp/2017/0701/p29.html)
`
`KALYANAKRISHNAN RAMAKRISHNAN, MD, and DEWEY C. SCHEID, MD, MPH, University of Oklahoma
`Health Sciences Center, Oklahoma City, Oklahoma
`
`Am Fam Physician. 2007 Aug 15;76(4):517-526.
`
`  Patient information: See related handout on insomnia (https://www.aafp.org/afp/2007/0815/p527.html), written
`by the authors of this article.
`
`The frequency of sleep disruption and the degree to which insomnia significantly affects daytime
`function determine the need for evaluation and treatment. Physicians may initiate treatment of
`insomnia at an initial visit; for patients with a clear acute stressor such as grief, no further evaluation
`may be indicated. However, if insomnia is severe or long-lasting, a thorough evaluation to uncover
`coexisting medical, neurologic, or psychiatric illness is warranted. Treatment should begin with
`nonpharmacologic therapy, addressing sleep hygiene issues and exercise. There is good evidence
`supporting the effectiveness of cognitive behavior therapy. Exercise improves sleep as effectively as
`benzodiazepines in some studies and, given its other health benefits, is recommended for patients
`with insomnia. Hypnotics generally should be prescribed for short periods only, with the frequency
`and duration of use customized to each patient's circumstances. Routine use of over-the-counter
`drugs containing antihistamines should be discouraged. Alcohol has the potential for abuse and
`should not be used as a sleep aid. Opiates are valuable in pain-associated insomnia.
`Benzodiazepines are most useful for short-term treatment; however, long-term use may lead to
`adverse effects and withdrawal phenomena. The better safety profile of the newer-generation non-
`benzodiazepines (i.e., zolpidem, zaleplon, eszopiclone, and ramelteon) makes them better first-line
`choices for long-term treatment of chronic insomnia.
`
`The American Academy of Sleep Medicine denes insomnia as unsatisfactory sleep that impacts
`daytime functioning.1 More than one third of adults report some degree of insomnia within any given
`year, and 2 to 6 percent use medications to aid sleep.2 Insomnia is associated with increased morbidity
`and mortality caused by cardiovascular disease and psychiatric disorders and has other major public
`health and social consequences, such as accidents and absenteeism.3 Risk factors for chronic
`insomnia include increasing age, female sex, psychiatric illness, medical comorbidities, impaired social
`relationships, lower socioeconomic status, separation from a spouse or partner, and unemployment.4
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`EISAI EXHIBIT 1026
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`SORT: KEY RECOMMENDATIONS FOR PRACTICE
`
`CLINICAL RECOMMENDATION
`
`View/Print Table
`
`EVIDENCE
`RATING
`
`REFERENCES
`
`Exercise, cognitive behavior therapy, and relaxation therapy are
`recommended as effective, nonpharmacologic treatments for chronic
`insomnia.
`
`Melatonin is effective in patients with circadian rhythm sleep disorders
`and is safe when used in the short term.
`
`Benzodiazepines are effective for treating chronic insomnia but have
`signicant adverse effects and the risk of dependency.
`
`Nonbenzodiazepines (e.g., eszopiclone [Lunesta], zaleplon [Sonata],
`zolpidem [Ambien]) are effective treatments for chronic insomnia and,
`based on indirect comparisons, appear to have fewer adverse effects
`than benzodiazepines.
`
`A
`
`B
`
`B
`
`B
`
`4, 7, 12,
`16
`
`20
`
`4, 22, 36
`
`4
`
`A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented
`evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For
`information about the SORT evidence rating system, see page 483 or https://www.aafp.org/afpsort.xml
`(https://www.aafp.org/afpsort.xml).
`
`Evaluation
`Criteria for the diagnosis of insomnia are provided in Table 1.5  Although there are several classication
`systems, it is practical to divide insomnia into two categories by duration: acute (i.e., less than 30 days)
`and chronic (i.e., 30 days or longer). If insomnia is associated with another condition, it is designated as
`comorbid insomnia (Table 2).6–8 Only about 15 to 20 percent of patients with chronic insomnia have no
`other associated diagnosis (primary insomnia).9
`
`View/Print Table
`
`Table 1
`Criteria for the Diagnosis of Insomnia
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`At least one of the following complaints:
`
`Difculty initiating and/or maintaining sleep; sleep that is poor in quality; trouble sleeping despite
`adequate opportunity and circumstances for sleep; waking up too early
`
`At least one of the following types of daytime impairment related to sleep difficulty:
`
`Attention, concentration, or memory impairment; concerns or worries about sleep; daytime
`sleepiness; errors or accidents at work or while driving; fatigue or malaise; gastrointestinal
`symptoms; lack of motivation; mood disturbance or irritability; social or vocational dysfunction or
`poor school performance; tension headaches
`
`Information from reference 5.
`
`Table 2
`Types and Causes of Insomnia
`
`Selected causes of acute insomnia (< 30 days)*
`
`View/Print Table
`
`Situational stress (e.g., occupational, interpersonal, nancial, academic, medical)
`
`Environmental stressors (e.g., noise)
`
`Death or illness of a loved one
`
`Selected causes of chronic insomnia (≥ 30 days)
`
`Medical disorders
`
`Arthropathies, cancer, chronic pain, congestive heart failure, COPD, end-stage renal disease,
`gastroesophageal reflux disease, HIV/AIDS, hyperthyroidism, nocturia caused by prostatic
`hypertrophy, stroke
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`Medications
`
`Anticholinergic agents; antidepressants (SSRIs, bupropion [Wellbutrin]), MAOIs; antiepileptics
`(lamotrigine [Lamictal], phenytoin [Dilantin]); antineoplastics; beta blockers; bronchodilators
`(beta agonists); CNS stimulants (methylphenidate [Ritalin], dextroamphetamine [Dextrostat],
`nicotine [Nicotrol]); interferon alfa; miscellaneous (diuretics, atorvastatin [Lipitor], levodopa,
`quinidine); steroids, oral contraceptives, progesterone, thyroid hormone
`
`Primary sleep disorder
`
`Periodic limb movement disorder, restless legs syndrome, sleep apnea
`
`Psychiatric disorders
`
`The frequency of sleep disruption and the degree to which insomnia signicantly affects daytime
`function (e.g., quality of life, work limitations, mood/social life) are probably the most important
`determinants of the need for evaluation and treatment. If the initial evaluation identies an acute
`stressor such as grief or noise, no further evaluation is indicated and treatment can be initiated. A more
`comprehensive evaluation should be pursued with nonresponders or if a comorbid condition is present
`or suspected.
`
`The evaluation of chronic insomnia should involve a detailed history and examination to detect any
`coexisting medical or psychiatric illness and may include an interview with a partner or caregiver.
`Evaluation should include an assessment of sleep dysfunction and a sleep diary (Table 3).3,8,10
`Following this evaluation, the need for further testing or pharmacotherapy can be determined.3,8,10,11
`
`View/Print Table
`
`Table 3
`Evaluation of Insomnia
`
`History and examination
`
`Helps detect any coexisting medical or psychiatric illness
`
`Sleep history must span the entire day and should include an interview with the partner or
`caregiver
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`Interview partner or caregiver about patient's sleep habits, daytime functioning, substance use
`(e.g., alcohol, tobacco, caffeine), snoring, apnea, and unusual limb movement
`
`Take medication history; physical examination should include neurologic examination, Mini-
`Mental State Examination
`
`Sleep diary
`
`A two-week sleep diary should record information on bedtime, rising time, daytime naps, sleep-
`onset latency, number of nighttime awakenings, total sleep time, and the patient's mood on
`arousal
`
`Questions should include daytime symptoms such as somnolence and frequency of napping
`
`Polysomnography, multiple sleep latency testing
`
`Useful if sleep apnea or periodic limb movement disorder is suspected
`
`Use when behavioral and psychopharmacologic treatments are unsuccessful
`
`Actigraphy
`
`An activity monitor or motion detector typically worn on the wrist records movement; the
`Treatment Overview
`Ideally, treatment for insomnia would improve sleep quantity and quality, improve daytime function
`(greater alertness and concentration), and cause minimal adverse drug effects. An approach to the
`evaluation and treatment of the patient with insomnia is shown in Figure 1. Most experts recommend
`starting with nonpharmacologic therapy (Table 4).4,7,12–17 Good evidence supports a benet for
`relaxation therapy and cognitive behavior therapy (CBT)4,12 that may be sustained over six to 24
`months.13–15 Exercise improves sleep as effectively as benzodiazepines in some studies and, given its
`other health benets, is recommended for patients with insomnia.7,16 Behavioral and cognitive
`interventions have minimal risk of adverse effects, but disadvantages include high initial cost, lack of
`insurance coverage, few trained therapists, and decreased effectiveness in older adults.17
`
`View/Print Figure
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`Evaluation and Treatment of Insomznia
`Figure 1.
`Approach to the evaluation and treatment of the patient with insomnia. (BPH = benign prostatic
`hypertrophy; CHF = congestive heart failure; MSLT = multiple sleep latency test.)
`
`View/Print Table
`
`Table 4
`Nonpharmacologic Treatments for Insomnia
`
`TREATMENT
`
`DESCRIPTION
`
`Cognitive
`behavior
`therapy
`
`Helps change incorrect beliefs and attitudes about sleep (e.g., unrealistic
`expectations, misconceptions, amplifying consequences of sleeplessness);
`techniques include reattribution training (i.e., goal setting and planning coping
`responses), decatastrophizing (aimed at balancing anxious automatic thoughts),
`reappraisal, and attention shifting
`
`Exercise
`
`Moderate-intensity exercise (should not occur just before bedtime)
`
`Relaxation
`therapy
`
`Tensing and relaxing different muscle groups; biofeedback or imagery (visual and
`auditory feedback) to reduce somatic arousal; meditation; hypnosis
`
`Sleep
`restriction
`(paradoxical
`intention
`therapy)
`
`Stimulus
`control
`therapy
`
`Uses a paradoxical approach in which the patient spends less time in bed (by
`associating time spent in bed with time spent sleeping)
`
`Bedtimes are then increased or decreased progressively depending on
`improvement or deterioration of sleep quality and duration
`
`This state of minimal sleep deprivation eventually leads to more efcient sleep
`
`Avoid bright lights (including television); noise and temperature extremes; and
`large meals, caffeine, tobacco, and alcohol at night
`
`Minimize evening fluid intake; leave the bedroom if unable to fall asleep within 20
`minutes; limit use of the bedroom to sleep and intimacy
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`TREATMENT
`
`DESCRIPTION
`
`Consistent time of wakening; minimal daytime napping
`
`Temporal
`control
`Pharmacologic Therapy
`Hypnotics are recommended when immediate symptom response is desired, when insomnia produces
`serious impairment, when nonpharmacologic measures do not produce the desired improvement, or
`when insomnia persists after treatment of an underlying medical condition. Table 5 outlines prescribing
`guidelines for hypnotics.18
`
`View/Print Table
`
`Table 5
`Guidelines for Prescribing Hypnotics
`
`Initiate hypnotic use with identifying and addressing specic behaviors, circumstances, and
`underlying disorders contributing to insomnia
`
`Prescribe the lowest effective dose of the hypnotic
`
`Prescribe hypnotics for short durations (two to four weeks) and intermittently (duration based on
`patient's return to an acceptable sleep cycle)
`
`Avoid hypnotic use or exercise caution if patient has a history of substance abuse, myasthenia
`gravis, respiratory impairment, or acute cerebrovascular accident
`
`Watch for requests for escalating doses or resistance to tapering or discontinuing hypnotic
`
`Hypnotics should be discontinued gradually (i.e., tapered); physician should be alert for adverse
`effects (especially rebound insomnia) and withdrawal phenomena
`
`Information from reference 18.
`
`ANTIHISTAMINES
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`Nearly 25 percent of patients with insomnia use over-the-counter (OTC) sleep aids, and 5 percent use
`them at least several nights a week. Routine use of OTC antihistamines such as diphenhydramine
`(Benadryl) and doxylamine (Unisom) should be discouraged because they are only minimally effective
`in inducing sleep, may reduce sleep quality, and can cause residual drowsiness.3,8
`
`HERBAL AND DIETARY SUPPLEMENTS
`
`Many herbs and dietary supplements (e.g., valerian root, melatonin, lavender, passionflower, kava, St.
`John's wort, glutamine, niacin, and L-tryptophan) have been promoted as sleep aids.19 There is
`insufcient evidence of benet except for melatonin and valerian.
`
`Melatonin, a hormone produced by the pineal gland that is involved in sleep regulation, improves
`insomnia caused by circadian schedule changes (e.g., jet lag, shift work).20  Melatonin has been
`approved by the U.S. Food and Drug Administration (FDA) to treat circadian rhythm sleep disorder in
`blind children and adults, but it is unregulated and preparations vary greatly in strength. At higher
`doses, it causes sleep disruption, daytime fatigue, headache, dizziness, and irritability (Table 6). Little
`information is available about the safety of long-term use.
`
`Table 6
`Pharmacologic Treatment of Insomnia
`
`DRUG
`
`DAILY
`DOSAGE
`(MG)
`
`PEAK
`ACTION
`(HOURS)
`
`HALF-
`LIFE
`(HOURS)
`
`COST, 30
`DAYS
`(GENERIC)*
`
`ADVERSE EFFECTS AND
`CONSIDERATIONS
`
`FDA
`APPROV
`
`View/Print Table
`
`Nonbenzodiazepines†
`
`Zolpidem
`(Ambien)
`
`5 to
`10
`
`0.5
`
`2 to 3
`
`$102
`
`Yes
`
`Abdominal pain,
`rebound insomnia;
`controlled-release
`formulation better for
`sleep maintenance;
`FDA pregnancy risk
`category B (not
`controlled-release
`formulation); CYP3A4-
`dependent metabolism
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`DRUG
`
`Treatment Options for Insomnia - American Family Physician
`
`DAILY
`DOSAGE
`(MG)
`
`PEAK
`ACTION
`(HOURS)
`
`HALF-
`LIFE
`(HOURS)
`
`COST, 30
`DAYS
`(GENERIC)*
`
`ADVERSE EFFECTS AND
`CONSIDERATIONS
`
`FDA
`APPROV
`
`Zaleplon
`(Sonata)
`
`5 to
`10
`
`0.5
`
`1
`
`103
`
`Eszopiclone
`(Lunesta)
`
`2 to 3
`
`1
`
`4 to 6
`
`121
`
`Yes
`
`Yes
`
`Better for sleep
`maintenance; altered
`color perception;
`CYP3A4- dependent
`metabolism
`
`Unpleasant taste (8 to
`24 percent), amnesia,
`hallucinations,
`worsening depression;
`CYP3A4-dependent
`metabolism
`
`Valerian root causes central sedation by inhibiting the breakdown of γ-aminobutyric acid (GABA) or its
`metabolites. There is minimal evidence for its effectiveness in treating insomnia.4 Residual daytime
`sedation and, rarely, hepatotoxicity are adverse effects. Preparations are unregulated by the FDA and
`may vary in valerian content.
`
`ALCOHOL
`
`At least 10 percent of young adults use OTC medications or alcohol in any given year to improve sleep.
`Alcohol, a central nervous system (CNS) stimulant and depressant, acts directly on GABA-gated
`channels reducing sleep-onset latency, but it also increases wakefulness after sleep onset and
`suppresses rapid eye movement (REM) sleep. Alcohol has the potential for abuse and should not be
`used as a sleep aid.
`
`BARBITURATES, OPIATES, AND ANTIDEPRESSANTS
`
`Barbiturates function as GABA brain receptor agonists, decreasing sleep-onset latency and
`A
`suppressing REM sleep. They are effective in short-term insomnia (i.e., up to two weeks) but lose the
`ability to induce and maintain sleep beyond this period.21 Longer-term use (i.e., more than two weeks)
`is associated with tolerance, physical and psychological dependence, and increased adverse effects
`(i.e., agitation, confusion, nightmares, hallucinations, lethargy, and hangover). Barbiturates should rarely
`be used as sleep aids.
`
`Opiates fragment sleep and decrease REM and stage 2 sleep. By producing analgesia and sedation,
`opiates may be appropriate in carefully selected patients with pain-associated insomnia.
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`Some antidepressants (e.g., amitriptyline, doxepin, trazodone [Desyrel], mirtazapine [Remeron]) produce
`sedation by blocking acetylcholine, norepinephrine, and serotonin presynaptic receptors. Compared
`with placebo, antidepressants decrease sleep-onset latency and wakefulness after sleep onset (Table
`7).4,13,14,16,22 They also increase total sleep time, sleep efciency, and sleep quality but suppress REM
`sleep.4 Antidepressants are an effective treatment option in patients with insomnia and coexisting
`depression. Trazodone is the most commonly prescribed sleep aid, but there is insufcient evidence to
`support its use in the absence of depression.
`
`BENZODIAZEPINE HYPNOTICS
`
`Benzodiazepines bind to GABA and GABA receptors, acting as agonists. They have less risk of
`A
`overdose and abuse potential than barbiturates. Benzodiazepines increase sleep time and improve
`sleep quality by reducing sleep-onset latency and wakefulness after sleep onset and by increasing
`sleep efciency (Table 7).4,13,14,16,22 However, they also potentiate CNS depression with alcohol or
`other sedatives. Benzodiazepines that have been approved by the FDA for treating chronic insomnia
`include estazolam, flurazepam (Dalmane), temazepam (Restoril), quazepam (Doral), and triazolam
`(Halcion). Rapidly acting drugs with shorter half-lives (i.e., estazolam, triazolam, and temazepam) are
`preferred. Temazepam has a slower onset of action and is less effective for initiating sleep. Flurazepam
`and quazepam have half-lives longer than 24 hours.
`
`Table 7
`Indirect Comparisons of the Effectiveness of Treatments for Insomnia
`
`TREATMENT
`
`SOL
`(MINUTES)
`
`WASO
`(MINUTES)
`
`SLEEP
`EFFICIENCY
`(%)*
`
`TOTAL
`SLEEP
`TIME
`INCREASE
`(MINUTES)
`
`SLEEP
`QUALITY
`(SMD)
`
`RISK
`DIFFERENCE†
`
`View/Print Table
`
`Nonpharmacologic13,14
`
`−15.7
`to −24
`
`−22.5
`
`—
`
`24.3 to
`32
`
`—
`
`Relaxation4
`
`−14.5
`
`−1.6
`
`Cognitive/behavioral4
`
`−4.6
`
`−18.2
`
`Exercise16
`
`−12
`
`—
`
`0.4
`
`5.5
`
`—
`
`23.0
`
`0.7
`
`42
`
`0.37
`
`0.38
`
`—
`
`—
`
`—
`
`—
`
`—
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`TREATMENT
`
`SOL
`(MINUTES)
`
`WASO
`(MINUTES)
`
`SLEEP
`EFFICIENCY
`(%)*
`
`Benzodiazepines4,22
`
`−4.2 to
`−16.5
`
`−23.1
`
`6.3
`
`TOTAL
`SLEEP
`TIME
`INCREASE
`(MINUTES)
`
`39.1 to
`61.8
`
`SLEEP
`QUALITY
`(SMD)
`
`RISK
`DIFFERENCE†
`
`0.08
`
`0.15
`
`Estazolam4
`
`−10.2
`
`—
`
`Flurazepam
`(Dalmane)4
`
`Temazepam
`(Restoril)4
`
`−23.1
`
`−12.4
`
`−11.6
`
`−23.7
`
`Triazolam (Halcion)4
`
`−19.7
`
`−40.0
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`Because tolerance and dependence occur with prolonged use, benzodiazepines are most useful for the
`short-term treatment of insomnia.22 Using benzodiazepines for more than four weeks increases the
`likelihood of dependence (dened as a compulsive or chronic need) and withdrawal phenomena
`(dened as a symptom complex that develops following discontinuation). An estimated 10 to 30
`percent of chronic benzodiazepine users develop dependence, and 50 percent suffer withdrawal.23
`Dependence is more likely with daily use for more than four months, with higher doses, in older
`patients, in patients with previous hypnotic or alcohol dependence, and when using high-potency,
`shorter- acting benzodiazepines.17
`
`Benzodiazepine withdrawal may cause anxiety, depression, nausea, perceptual changes, rebound
`insomnia, intense dreams, nightmares, and poor memory consolidation. Withdrawal symptoms may
`develop within a few hours of discontinuing a short-acting benzodiazepine, or up to three weeks after
`discontinuing a long-acting benzodiazepine.23 Although often recommended, gradually tapering the
`dose alone is ineffective in achieving long-term discontinuation.24 However, combining CBT with
`tapering of benzodiazepines results in successful discontinuation in 70 percent of patients at 12
`months.24
`
`With short-acting drugs, rebound insomnia can occur the same night the drug is administered, leading
`to ante-grade memory impairment. Their use increases the risk of motor vehicle collisions, falls and
`serious injuries, and fatal overdose in older adults.25–27 All benzodiazepines may cause respiratory
`depression in patients with pulmonary disease.
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`NONBENZODIAZEPINE HYPNOTICS
`
`The newer nonbenzodiazepines selectively bind to type 1 benzodiazepine receptors in the CNS. Unlike
`benzodiazepines, the nonbenzodiazepines have minimal impact on sleep stages and no REM sleep
`rebound. Tachyphylaxis is unusual. Nonbenzodiazepines undergo hepatic degradation, and doses
`should be reduced in older patients and in those with hepatic dysfunction.28 Direct comparisons of
`nonbenzodiazepines and benzodiazepines are not available. However, when indirectly compared, the
`nonbenzodiazepines are similarly effective but have less overall risk of adverse effects.29 Nevertheless,
`these newer agents can cause impaired memory and psychomotor retardation.30 Nonbenzodiazepine
`hypnotics approved by the FDA for the treatment of insomnia include zolpidem (Ambien), zaleplon
`(Sonata), and eszopiclone (Lunesta).
`
`Zolpidem
`Zolpidem decreases sleep-onset latency, improves sleep quality, increases stage 2 and slow-wave
`sleep, and does not exhibit tolerance or rebound following ve weeks of continuous use at
`recommended dosages.4,29 Adverse effects occur at daily dosages of 20 mg or more. Because of its
`longer half-life, a controlled-release version (Ambien CR) in a dosage of 6.25 to 12.5 mg daily may be
`better for maintaining sleep, but it should not be readministered following nocturnal awakenings and
`has not been shown to reduce adverse effects.17 Direct comparisons of zolpidem with controlled-
`release zolpidem have not been published.
`
`Zaleplon
`Zaleplon decreases sleep-onset latency. Its short half-life (i.e., one hour) enables readministration
`following nocturnal awakenings. It is particularly useful in patients who have trouble falling asleep and
`maintaining sleep and can be administered up to four hours before the anticipated wake time.17
`Zaleplon causes less memory and psychomotor impairment than do benzodiazepines and zolpidem.28
`Some patients report visual disturbances, such as a change in color perception.
`
`Eszopiclone
`Eszopiclone, an isomer of zopiclone, is the only hypnotic with FDA approval for use longer than 35 days.
`Eszopiclone has evidence of effectiveness for six months of therapy in a randomized, placebo-
`controlled trial, although there is some attenuation of its effect over time.31 It produces signicant and
`sustained decreases in sleep-onset latency, wake time, number of awakenings, and number of nights
`awakened per week; it also improves total sleep time and quality of sleep.31 Eszopiclone has not been
`directly studied in comparison to other hypnotics or nonpharmacologic therapy. Higher doses (2 to 3
`mg) are more effective for sleep maintenance, whereas lower doses (1 to 2 mg) are suitable for
`difculty in falling asleep. The onset of action may be delayed if eszopiclone is taken with a high-fat
`meal. Rare cases of fatal overdose when used with other CNS depressants have been reported.
`
`RAMELTEON (ROZEREM)
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`Ramelteon is a selective melatonin receptor agonist targeting the melatonin MT and MT receptors in
`1
`2
`the brain. It reduces sleep-onset latency and increases sleep periods.32 However, patient evaluations of
`improvement are inconsistent and there are no comparison studies. Ramelteon has not been studied in
`patients with depression, anxiety, shift work, or jet lag.33 There is a low likelihood of abuse and physical
`dependence. Serious adverse effects attributed to ramelteon are rare, affecting less than 1 percent of
`patients. Common side effects include somnolence, headache, fatigue, nausea, and dizziness. The
`metabolism of ramelteon is reduced in patients with severe hepatic impairment. Ramelteon is the only
`non-scheduled drug for insomnia.
`
`COMBINATION THERAPY
`
`There is little evidence to support combining nonpharmacologic and pharmacologic treatments for
`insomnia. The results of one study that compared benzodiazepine plus CBT versus benzodiazepine
`alone showed that sleep efciency was minimally improved with the use of combination therapy.34
`Wakefulness after sleep onset and total sleep time were not signicantly different. Another study that
`compared CBT plus zolpidem, CBT alone, zolpidem alone, and placebo found improvements in sleep-
`onset latency in the CBT-only group. The authors of a third study that compared benzodiazepine plus
`CBT versus CBT alone found no differences in sleep outcomes.34
`
`Treatment Comparisons
`A meta-analysis comparing pharmacologic and nonpharmacologic treatments found similar short-term
`effectiveness (two to four weeks) in patients with primary insomnia. Nonpharmacologic therapy
`showed slightly greater reductions in sleep-onset latency, but wakefulness after sleep onset, number of
`awakenings, total sleep time, and sleep quality were not signicantly different.15
`
`There are no direct comparisons of the effectiveness of the newer nonbenzodiazepines and other
`medications for chronic insomnia. Indirect comparisons in which each medication was compared with
`placebo are shown in Table 7.4,13,14,16,22 In one meta-analysis, use of nonbenzodiazepines did not
`signicantly reduce sleep-onset latency compared with benzodiazepines; however, a signicant
`reduction was noted when nonbenzodiazepines were compared with antidepressant and melatonin
`therapies.8 Zolpidem and benzodiazepine therapies were equally effective compared with placebo for
`patients 65 years or younger.35 In a meta-analysis of patients 60 years and older with insomnia,
`researchers found that benzodiazepines and nonbenzodiazepines were associated with an increased
`risk of adverse events.36
`
`The abuse potential of hypnotics is often overstated. Most patients taking hypnotics do so for a short
`period; only 10 to 15 percent take hypnotics long-term. Although substance abusers may abuse
`benzodiazepines, they rarely abuse nonbenzodiazepines.37 Hypnotic overdose is generally not life-
`threatening unless more than one drug in a class or opiates are also ingested.
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`The cost of nonbenzodiazepines is considerably higher than benzodiazepines. An economic evaluation
`comparing the cost-effectiveness of nonpharmacologic treatment, benzodiazepines, eszopiclone, and
`no treatment in older adults found that, compared with benzodiazepines, nonpharmacologic therapy
`(i.e., CBT) produced a net gain of 0.37 quality-adjusted life-years at a savings of $2,781 over 10 years.38
`
`The Authors show all author info
`KALYANAKRISHNAN RAMAKRISHNAN, MD, is an associate professor in the Department of Family and
`Preventive Medicine at the University of Oklahoma Health Sciences Center, Oklahoma City. Dr.
`Ramakrishnan received his medical degree from Jawaharlal Institute of Postgraduate Medical
`Education and Research, Pondicherry, India, and completed a family practice residency at the University
`of Oklahoma Health Sciences Center....
`
`REFERENCES
`
`show all references
`
`1. Sateia MJ, Doghramji K, Hauri PJ, Morin CM. Evaluation of chronic insomnia. An American Academy
`of Sleep Medicine review. Sleep. 2000;23:243–308....
`
`This is one in a series of “Clinical Pharmacology” articles coordinated by Allen F. Shaughnessy, PharmD,
`Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Mass.
`
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