eMedicine Specialties > Psychiatry > Adult

Primary Insomnia

Catherine McVearry Kelso, MD,, Assistant Professor of Internal Medicine, Virginia Commonwealth University; Medical Director, Hospice and Palliative Care, Hunter Holmes McGuire VA Medical Center, Richmond
Angela Gentili, MD, Director of Geriatrics Fellowship Program, Associate Professor, Department of Internal Medicine, Virginia Commonwealth University Health System and McGuire Veterans Affairs Medical Center; Antony Fernandez, MD, FRCPsych (UK), Associate Professor, Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University; Acting Director, Sleep Disorders Clinic, McGuire Veterans Affairs Medical Center, Richmond

Updated: Jun 5, 2009

Introduction

Background

Primary insomnia is sleeplessness that is not attributable to a medical, psychiatric, or environmental cause. The diagnostic criteria for primary insomnia (307.42) from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) are as follows:

• The predominant symptom is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 1 month.
• The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia.
• The disturbance does not occur exclusively during the course of another mental disorder (eg, major depressive disorder, generalized anxiety disorder, a delirium).
• The disturbance is not due to the direct physiological effects of a substance (eg, drug abuse, medication) or a general medical condition.^{[1 ]}

The International Classification of Sleep Disorders (ICSD-2) diagnostic and coding manual consists of 3 primary insomnia categories: 

• Psychophysiological insomnia
• Idiopathic insomnia
• Paradoxical insomnia^{[2,3 ]}

Case study

A 56-year-old woman reports difficulty falling asleep and staying asleep. She reports intermittent episodes of sleep difficulty during periods of stress. However, for the past 3 weeks she has not been able to sleep well and frequently takes 90 minutes to fall asleep and then wakes within 2 hours and is not able to return to sleep. Her excessive daytime sleepiness has interfered with her work as an artist. She denies stress and depression and has no significant medical history.

Pathophysiology

The pathophysiology of primary insomnia is not well understood and essential features assist with diagnosis. The focus of management is on symptoms.
 
Psychophysiological insomnia
 
The essential features include learned or behavioral insomnia and heightened arousal.
 
The primary components involved are intermittent periods of stress that result in poor sleep and maladaptive behaviors. These include (1) a vicious cycle of trying harder to sleep and becoming tenser (ie, patients “trying too hard to sleep”) and (2) bedroom habits and routines (eg, brushing teeth) that actually condition the patient to become frustrated and aroused. Patients often report "racing thoughts" and sensitivity to their environment. 
 
Bad sleep habits such as those naturally acquired during periods of stress are occasionally reinforced. These are therefore not resolved and become persistent. Insomnia continues for years after the stress is abated and is labeled persistent psychophysiological insomnia. 
 
Idiopathic insomnia
 
The essential feature of idiopathic insomnia is lifelong sleeplessness with onset in infancy or childhood. 
 
Lifelong sleeplessness is attributed to an abnormality in the neurologic control of the sleep-wake cycle for many areas of the reticular activating system (which promotes wakefulness) as well as in areas such as supra nuclei, raphe nuclei, and medial forebrain areas (which promote sleep).
 
Possibly, a so-called neuroanatomic, neurophysiologic, or neurochemical lesion exists in the sleep state that patients tend to be on the extreme end of the spectrum toward arousal.
 
Paradoxical insomnia
 
Paradoxical insomnia is also called sleep state misperception. The essential feature is reports of severe insomnia without supporting objective evidence such as daytime sleepiness.

Frequency

United States

Primary insomnia is diagnosed in approximately 15-25% of patients with insomnia who are referred to sleep disorder centers following exclusion of other predisposing conditions. However, true incidence is not known. Primary insomnia is estimated to occur in 25% of all patients with chronic insomnia.

Mortality/Morbidity

Whether the consequences associated with chronic insomnia outweigh the costs of treatment remains debatable. Despite that, the following associations have been noted:

• Increased risk of mortality is associated with short sleep lengths.
• Insomnia is the best predictor of the future development of depression.
• Catastrophic worry about the consequences of not sleeping is common among patients with chronic insomnia and serves to maintain the sleep disturbance.
• Increased risk exists of developing anxiety, alcohol and drug use disorders, and nicotine dependence.
• Poor health and decreased activity occur.
• Onset of insomnia in older patients is related to decreased survival.

Sex

Primary insomnia is more common in women than in men.

Age

Persons of any age may be affected, although primary insomnia is more common in the older population.

Clinical

History

A thorough clinical interview with the patient and his or her sleep partner is critical in making the correct diagnosis of primary insomnia.

• Psychophysiological insomnia
  • Sleep disturbance varies from mild to severe.
  • Insomnia may manifest as difficulty falling asleep or as frequent nocturnal awakenings.
  • Patients often find that they can sleep well anywhere else but in their own bedroom (see Pathophysiology).
  • Patients with this type of insomnia tend to be more tense and dissatisfied compared to people who sleep well. Emotionally, they typically are repressors, denying problems.
• Idiopathic insomnia
  • Insomnia is long-standing, typically beginning in early childhood.
  • Patients often present with other hard-to-localize neurologic signs and symptoms such as difficulties with attention or concentration, hyperactivity, and mild nonfocal electroencephalographic abnormalities.
  • Emotionally, persons with childhood-onset insomnia are often repressors, denying and minimizing emotional problems.
  • These individuals often show atypical reactions, such as hypersensitivity or insensitivity, to medications.
  • Insomnia tends to persist over the entire life span and can be aggravated by stress or tension.
• Sleep state misperception: Patients report insomnia subjectively, while sleep duration and quality are completely normal.

Physical

Physical findings that indicate sleep deprivation and fatigue may include features such as eye redness. Depending on the origin of the sleep dysfunction, other physical findings would be included to rule out secondary causes (ie, weight, neck circumference, thyroid). A complete neurologic examination is included in the evaluation of insomnia to assess for comorbid conditions. Recognition of mental disorders that may be contributing to insomnia is key to effectively manage symptoms.^{[4 ]}

When performing a complete Mental Status Examination, drowsiness and mood changes such as irritability, anxiety, and sad feelings from underlying depression may be noted. The clinician should also note the patient's orientation, memory, judgment, insight, and the presence of any hallucinations or delusions.^{[5 ]}

As with any mental status (but especially with the concern about depression), assess the patient's suicide potential. For completeness, assess the patient's homicidal potential as well.

Causes

Exclusion of other common causes is required to make the diagnosis of primary insomnia.

• Medical causes
  • Chronic pain, especially neuropathic pain
  • Primary sleep disorders (eg, sleep apnea, periodic limb movements, restless legs syndrome)
  • Dyspnea from any cause
  • Pregnancy
  • Drug use or withdrawal (eg, selective serotonin reuptake inhibitors, stimulants, antihistamines, caffeine, diet pills, herbal preparations containing ma huang, anticonvulsants, steroids)
• Psychiatric and/or psychological causes
  • Mood disorders (eg, depression, mania): Recent findings have strengthened the evidence that primary insomnia may be linked with mood disorders and is associated with hypothalamic-pituitary-adrenal (HPA) axis overactivity and excess secretion of corticotropin-releasing factor (CRF), adrenocorticotropin-releasing hormone, and cortisol.
  • Anxiety disorders (eg, generalized anxiety, panic attacks, obsessive–compulsive disorder)
  • Substance abuse (eg, alcohol or sedative/hypnotic withdrawal)
  • Major life stressors and/or events
• Environmental causes
  • Noise
  • Jet lag or shift work
  • Bedroom too hot or cold

Differential Diagnoses

Other Problems to Be Considered

A number of occult medical, psychiatric, and substance abuse disorders can cause sleep disturbance. Also consider other sleep-related disorders, such as circadian rhythm sleep disorder and parasomnias, in the differential diagnosis. Substance abuse can cause insomnia during the intoxication phase, during the sustained use phase, and during withdrawal.

Workup

Laboratory Studies

• Laboratory studies essentially are not required for the diagnosis of primary insomnia.
• Tests required to exclude other causes of insomnia include the following:
  • Thyroid function tests (hyperthyroidism)
  • Blood alcohol levels (alcohol-related psychosis)

Imaging Studies

• Neuroimaging studies may be helpful if a structural lesion is suspected to cause insomnia.

Other Tests

• Sleep diary (see Media file 1)
  • This is a questionnaire completed by the patient each morning to describe the previous night's sleep.
  • Data from the sleep diary may help minimize distortions in sleep information recalled in the physician's office.
  • 
    

    

    Primary insomnia. Evaluation of insomnia. Format of sleep diary.

    
    
• Actigraphy: This is a recently developed technique that makes use of an activity monitor to record activities during sleep and waking. It is useful in the diagnosis of circadian rhythm sleep disorders, sleep state misperception, and other types of primary insomnia. In older adults treated for chronic primary insomnia, the clinical use of actigraphy is still suboptimal in detecting wakefulness.

Procedures

• The goal of insomnia management is to improve sleep quality and maintenance and limit daytime impairments.^{[6 ]}
• Full-night polysomnography (PSG) is indicated when suspicion of sleep apnea or movement disorders arises, when initial diagnosis is uncertain, when treatment fails, or when precipitous arousal occurs with violent or injurious behavior.^{[7,8,6 ]} 
• Multiple sleep latency test
  • Psychophysiological insomnia and idiopathic insomnia manifest as increased sleep latency, reduced sleep efficiency, and increased number and duration of awakenings.
  • Sleep state misperception manifests as normal sleep latency (15-20 min), normal number of arousals and awakenings, and normal sleep duration (6.5 h). The multiple sleep latency test shows normal daytime vigilance. Sleep state misperception can be diagnosed only in the laboratory because of the need to document that sleep duration and quality are normal when a person claims to have poor sleep.

Treatment

Medical Care

The goal of insomnia management is to improve sleep quality and maintenance and limit daytime impairments.

Nonprescription drugs

• The active agent in many over-the-counter medications is one of the sedating antihistamines. These medications are generally safe but have anticholinergic adverse effects, such as dry mouth, blurred vision, urinary retention, and confusion in older patients, that can be potentially more serious in patients with dental caries, glaucoma, prostatic enlargement, and dementia (or delirium), respectively.
• These medications are minimally effective in inducing sleep and may reduce sleep quality. Discourage patients from using them on a routine basis.
• The use of various herbal preparations (eg, herbal tea) and nutritional substances are reported to be beneficial by users but no supporting trials have been performed.
• Studies have shown that melatonin may be useful for short-term adaptation to jet lag or other circadian rhythm sleep disorders. One study showed that ramelteon, a highly selective agonist for melatonin subtypes 1 and 2 receptors, is a good option for the treatment of insomnia characterized by difficulty falling asleep. In patients with insomnia, treatment with ramelteon was generally well tolerated and resulted in modest but statistically significant decreases in the latent period for sleep.^{[9 ]} Ramelteon is the first FDA-approved melatonin receptor agonist drug.

Prescription drugs

• The American Academy of Sleep Medicine guidelines include the following recommendations for the pharmacologic management of primary insomnia, listed in the preferred medication sequence.^{[6 ]} 
  • Short- or intermediate-acting benzodiazepine receptor agonists (BzRAs), whether a benzodiazepine such as temazepam or a newer BzRA such as zolpidem, eszopiclone, or zaleplon
  • Other short- or intermediate-acting BzRAs or ramelteon if the initial agent was unsuccessful
  • Sedating low-dose antidepressant such as trazodone, nefazodone, amitriptyline, doxepin, and mirtazapine, especially in patients with depression or anxiety (Amitriptyline should not be used in older patients because of high anticholinergic side effect profile.)
  • Combination BzRA or ramelteon and sedating antidepressant
• According to evidence-based recommendations on sleep disorders in older persons published in the Journal of American Geriatrics Society in 2009, clinically significant adverse effects can be associated with all FDA-approved medications for the treatment of insomnia (evidence level A) and the safest and most effective medications currently available are nonbenzodiazepines and melatonin receptor agonists (evidence level B or moderate).^{[10 ]} Prescriptions not recommended include the following:^{[6 ]}
  • Choral hydrate, barbiturates, nonbarbiturate nonbenzodiazepine drugs (ie, meprobamate) due to significant adverse effects and tolerance.
  • Off-label use of antiepileptic (gabapentin, tiagabine) and atypical antipsychotics (quetiapine, olanzapine). Insufficient evidence of efficacy when used alone and adverse effects. May be considered for those with comorbid conditions and insomnia.
• Basic principles for rational treatment of insomnia are to use the lowest effective dose, use intermittent dosing (2-3 nights/wk), use short term (2-3 wk at a time), discontinue after slow taper if the patient has been taking it regularly, and use agents with short and/or intermediate half-life to minimize daytime sedation.
• Pharmacokinetic properties and risk-benefit ratio are the key factors in selecting the most appropriate medication. 

FDA-Approved Hypnotics for Insomnia

* Not FDA approved for sleep

• Common adverse effects of hypnotics are as follows:
  • Anterograde amnesia and withdrawal effects may occur, especially with short-acting BZD (not with zolpidem and zaleplon).
  • Residual daytime sedation with intermediate-acting and long-acting drugs may occur, depending on dosage and half-life.
  • Rebound insomnia may occur with short-acting and intermediate-acting BZD after discontinuation.
  • Dosage, pharmacokinetic properties, and risk-benefit ratio are the key factors in selecting the most appropriate medication.
  • Short-acting agents are recommended for patients with difficulty falling asleep, while intermediate-acting drugs are indicated for problems with sleep maintenance.
  • Avoid long-acting agents, especially in older people, because they cause daytime sedation, impair cognition, and thereby increase the risk of falls.
• Contraindications of these agents are as follows:
  • Pregnancy is a contraindication.
  • Untreated obstructive sleep apnea is a contraindication.
  • History of substance abuse is a contraindication.
  • Caution and close monitoring is needed in older people and in patients with hepatic, renal, or pulmonary disease.
• Nonpharmacologic treatment: Psychological treatment for insomnia consists primarily of patient education and short-term cognitive-behavioral therapies. The focus is primarily on sleep hygiene or factors presumed to perpetuate insomnia; as such, these therapies seek to modify maladaptive sleep habits and to educate patients about healthier sleep practices.
• Stimulus control therapy: The purpose is to reestablish the connection between the bed and sleep by prohibiting the patient from engaging in nonsleep activities while in bed. The instructions given to the patient are (1) to go to bed only when sleepy, (2) to use the bed and bedroom only for sleep and intimacy, (3) to avoid trying to force sleep (go into another room whenever unable to fall asleep within 20-30 min and return to bed only when sleepy again), (4) to get up at the same time each morning regardless of how much the patient slept the previous night, and (5) to avoid daytime napping.
• Sleep restriction therapy: This involves limiting the amount of time the patient spends in bed to the actual amount of time the patient usually spends sleeping. This results in sleep deprivation, which accumulates and causes more rapid sleep onset on subsequent nights. As sleep improves, the patient is allowed to gradually increase time in bed by 15-30 minutes.
• Relaxation therapies: Relaxation-based interventions are indicated based on the observation that patients with insomnia often display high levels of arousal (physiologic and cognitive) both at night and during the daytime. The various techniques available to deactivate the arousal system are (1) progressive muscle relaxation, (2) biofeedback, and (3) imagery training and thought stopping.
• Cognitive behavior therapy (CBT): This consists of identifying patient-specific dysfunctional sleep cognitions, challenging their validity, and replacing them with more adaptive substitutes such as reattribution training, reappraisal, and attention shifting. A recent randomized clinical trial determined that 4 individual, biweekly sessions represent the optimal dosing for cognitive behavioral intervention.^{[11 ]}
• Paradoxical intention: This method consists of persuading a patient to engage in his or her most feared behavior (ie, staying awake). This serves to eliminate performance anxiety so that sleep may come more easily.
• Combined therapy: CBT and hypnotic medications are efficacious for short-term treatment of insomnia, but few patients achieve complete remission with any single treatment. Morin et al studied 160 adults with persistent insomnia and demonstrated that CBT used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P <0.001). Combined therapy produced a higher remission rate compared with CBT alone during the 6-month extended therapy phase and the 6-month follow-up period (56% [43/74 and 32/59] vs 43% [34/75 and 28/68]; P = .05). Long-term outcome was optimized when medication was discontinued during maintenance CBT.^{[12 ]}

Consultations

Consultation with a sleep disorders specialist may be necessary if the standard pharmacologic and behavioral treatments are not effective.

Medication

The goals of pharmacotherapy for primary insomnia are to reduce morbidity and to prevent complications. In addition to the FDA-approved drugs listed below, new experimental drugs are being developed. Among them is indiplon, which is a unique nonbenzodiazepine experimental drug that acts on a specific site of the gamma-aminobutyric acid (GABA)-A receptor. Initial studies have shown significantly improved subjective measures of sleep induction and maintenance in elderly women with chronic insomnia at a dose of 5-10 mg.^{[13,14 ]}

Another class of drugs, the 5-HT _2A receptor, serotonin plays an active role in the regulation of sleep architecture and targets deeper slow wave sleep. Antagonists/inverse-agonists of 5-HT _2A , such as APD125, volinanserin, eplivanserin, pruvanserin, and pimavanserin, are currently being investigated.^{[15,16 ]}

A recent randomized, double-blind, placebo-controlled trial using low-dose doxepin for elderly patients with primary insomnia revealed improved sleep maintenance and some effect on sleep onset at doses of 1 mg, 3 mg and 6 mg with no anticholinergic side effects.^{[17 ]}

Benzodiazepine hypnotics

The primary indication is for short-term management of insomnia, either as the sole treatment modality or as adjunctive therapy until the underlying problem is controlled. Hypnotics can be useful in psychophysiological insomnia for particularly poor nights or when the subjects know ahead of time that they will encounter difficulty sleeping (eg, before an examination or a presentation). An occasional hypnotic can be used for sleep state misperception when the patient becomes extremely worried about perceived lack of sleep for several nights.

Flurazepam (Dalmane)

Long-acting BZD that acts through GABA receptor. Half-life is 48-120 h, and peak action is 0.5-1 h.

Dosing

Adult

15-30 mg PO hs prn

Pediatric

Not established

Interactions

Increased toxicity of BZDs in CNS with coadministration of phenothiazines, barbiturates, and alcohol

Contraindications

Documented hypersensitivity; untreated obstructive sleep apnea; history of substance abuse; narrow-angle glaucoma; preexisting CNS depression; respiratory depression

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution and close monitoring needed in low albumin levels and hepatic, renal, or pulmonary disease
Causes residual daytime sedation, impaired cognition, and increased risk of falls, especially in older people; caution with other CNS depressants

Quazepam (Doral)

Long-acting BZD that acts through BZD receptor. Half-life is 41 h, and peak action is 2 h.

Dosing

Adult

7.5-15 mg PO hs prn

Pediatric

Not established

Interactions

Increased toxicity of BZDs in CNS with coadministration of phenothiazines, barbiturates, and alcohol

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution and close monitoring needed in low albumin levels and hepatic, renal, or pulmonary disease
Causes residual daytime sedation, impaired cognition, and increased risk of falls, especially in older people; caution with other CNS depressants

Estazolam (ProSom)

Intermediate-acting BZD good for sleep maintenance. Half-life is 10-24 h, and peak action is 2 h.

Dosing

Adult

1-2 mg PO hs prn

Pediatric

Not established

Interactions

Increased toxicity of BZDs in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution and close monitoring needed in low albumin levels and hepatic, renal, or pulmonary disease
Causes residual daytime sedation, impaired cognition, and increased risk of falls, especially in older people; caution with other CNS depressants; residual daytime sedation and rebound insomnia after discontinuation is common

Temazepam (Restoril)

Intermediate-acting BZD good for sleep maintenance. Half-life is 3.5-18 h, and peak action is 1.2-1.6 h.

Dosing

Adult

7.5-30 mg PO hs prn

Pediatric

Not established

Interactions

Increased toxicity of BZDs in CNS with coadministration of phenothiazines, barbiturates, and alcohol

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse; severe uncontrolled pain

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution and close monitoring needed in low albumin levels and hepatic, renal, or pulmonary disease
Causes residual daytime sedation, impaired cognition, and increased risk of falls, especially in older people; caution with other CNS depressants

Lorazepam (Ativan)

Intermediate-acting BZD good for sleep maintenance. Usually used as an anxiolytic. Half-life is 10-20 h, and peak action is 2-4 h.

Dosing

Adult

0.5-2 mg PO hs prn

Pediatric

Not established

Interactions

Toxicity of BZDs in CNS increases when used concurrently with alcohol, phenothiazines, and barbiturates

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease

Triazolam (Halcion)

Short-acting BZD recommended for people with difficulty falling asleep. Half-life is 1.5-5.5 h, and peak action is 1-2 h.

Dosing

Adult

0.125-0.25 mg PO hs prn

Pediatric

Not established

Interactions

Increases toxicity of BZDs in CNS with coadministration of phenothiazines, barbiturates, and alcohol

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution and close monitoring needed in low albumin levels and hepatic, renal, or pulmonary disease
Causes residual daytime sedation, impaired cognition, and increased risk of falls, especially in older people; caution with other CNS depressants; rebound insomnia may occur after discontinuation; as a short-acting BZD, can cause amnesia if used in higher than recommended doses

Nonbenzodiazepine hypnotics

These agents are gaining popularity because they do not have significant effect on sleep architecture and are not associated with the rebound phenomenon seen with the benzodiazepines.

Eszopiclone (Lunesta)

Nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown but is believed to interact with GABA-receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. Indicated for insomnia to decrease sleep latency and improve sleep maintenance. Short half-life of 6 h. Higher doses (ie, 2 mg for elderly adults and 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg for elderly adults and 2 mg for nonelderly adults) are suitable for difficulty in falling asleep.

Dosing

Adult

Nonelderly adults: 2 mg PO hs; may increase to 3 mg PO hs prn
Elderly adults: 1 mg PO hs initially; not to exceed 2 mg PO hs
Severe hepatic impairment: Do not exceed 2 mg PO hs

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

CYP3A4 and CYP2E1 substrate; potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, nelfinavir) increase AUC, C_max, and t_1/2 and therefore potential toxicity (decrease dose); potent CYP3A4 inducers (eg, rifampicin) increase clearance; coadministration with alcohol or other CNS depressants may increase effect and toxicity (decrease dose); coadministration with olanzapine may decrease DSST scores; sleep onset may be delayed if taken with or immediately after a high-fat or heavy meal

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause dysgeusia, headache, or coldlike symptoms; rare adverse effects associated with hypnotics include short-term amnesia, confusion, agitation, hallucinations, worsened depression, or suicidal thoughts; high doses (ie, 6-12 mg) produce euphoric effects similar to those of diazepam 20 mg; anxiety, abnormal dreams, nausea, and upset stomach may occur within 48 h after discontinuing; alertness may be affected the following day, use caution while operating machinery or driving a car

Zolpidem (Ambien, Ambien CR)

This is in the class of imidazopyridines, structurally unrelated to BZDs. Recommended for people with difficulty falling asleep. Half-life is 2.5 h, and peak action is 1.6 h.
The extended-release product (Ambien CR) consists of a coated two-layer tablet and is useful for treating insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep, whereas the second layer gradually releases additional drug content to provide continuous sleep.

Dosing

Adult

5-10 mg PO hs prn
Extended-release: 12.5 mg PO hs
Extended-release in elderly patients: 6.25 mg PO hs

Pediatric

Not established

Interactions

Increases toxicity of alcohol and CNS depressants; effect may be delayed if taken with food or shortly after a meal

Contraindications

Documented hypersensitivity; lactation; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor elderly patients for impaired cognitive or motor performance; caution in hepatic, renal, or pulmonary disease; visual hallucinations are associated with rapid withdrawal and restarting of zolpidem; use of lowest effective dose may prevent hallucinations; extended-release dosage form must be swallowed whole (do not divide, chew, or crush)

Zaleplon (Sonata)

Imidazopyridine, structurally unrelated to BZDs. Recommended for people with difficulty falling asleep. Half-life is 0.5-1 h, and peak action is 0.5-1 h.

Dosing

Adult

5-10 mg PO hs prn; in patients with hepatic function impairment, reduce dose to 5 mg PO hs

Pediatric

Not established

Interactions

Cimetidine significantly increases levels of zaleplon

Contraindications

Documented hypersensitivity; pregnancy; untreated obstructive sleep apnea; history of substance abuse

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Failure of insomnia to remit after 7-10 d of treatment may indicate need for evaluation of a primary psychiatric or medical illness; limit treatment to 7-10 d and reevaluate patient if zaleplon is to be taken for >2-3 wk (do not prescribe in quantities exceeding a 1-mo supply); in hepatic function impairment, reduce dose to 5 mg PO hs; caution in patients exhibiting signs or symptoms of depression

Antidepressants

Indicated for use when insomnia is associated with psychiatric disorders or if the patient has a history of substance abuse. As with other antidepressants, little scientific evidence supports efficacy in the treatment of insomnia without associated depression.

Mirtazapine (Remeron, Remeron SolTab)

Exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, shown to be superior to other SSRI drugs.

Dosing

Adult

15 mg PO hs initially; may increase by 15 mg increments q1-2wk, not to exceed 45 mg hs

Pediatric

Not established

Interactions

May increase effect of CNS depressants; concurrent administration with MAOI may trigger hypertensive crisis

Contraindications

Documented hypersensitivity; MAOI within 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause drowsiness; discontinue use if patient develops sore throat, fever, or other signs of infection; suicide ideation is inherent in depression and may persist until significant remission occurs; severe neutropenia reported in clinical trials

Nefazodone (Serzone)

Sedating antidepressant; may be used in small dose at bedtime. Not associated with tolerance or withdrawal effects. Does not have anticholinergic adverse effects.

Dosing

Adult

50-100 mg PO hs prn

Pediatric

Not established

Interactions

Increases effects of digoxin, carbamazepine, triazolam, alprazolam, and protease inhibitors through its effect of inhibiting CYP3A4 enzyme; serotonin syndrome may occur when used with other serotonergic agents such as buspirone, meperidine, tramadol, dextromethorphan, triptans, mirtazapine, SSRIs, and especially with MAOIs

Contraindications

Documented hypersensitivity; MAOIs within 14 d of initiating treatment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiac disease, cerebrovascular disease, or seizures

Trazodone (Desyrel)

Sedating antidepressant that may be used in small dose at bedtime. Not associated with tolerance or withdrawal effects. Does not have anticholinergic adverse effects.

Dosing

Adult

50-100 mg PO hs prn

Pediatric

Not established

Interactions

Cimetidine significantly increases levels of trazodone; serotonin syndrome may occur when used with other serotonergic agents such as buspirone, meperidine, tramadol, dextromethorphan, triptans, mirtazapine, nefazodone, SSRIs, and especially with MAOIs

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Hypotension has occurred, including orthostatic hypotension and syncope; may produce drowsiness, dizziness, or blurred vision; patients taking this medication should be cautious while driving or performing other tasks requiring alertness, coordination, or dexterity; caution in cardiac disease, cerebrovascular disease, or seizures; discontinue therapy and reevaluate if priapism occurs

Melatonin agonists

Indicated for insomnia characterized by difficulty with sleep onset.

Ramelteon (Rozerem)

Melatonin receptor agonist with high selectivity for human melatonin MT₁ and MT₂ receptors. MT₁ and MT₂ are thought to promote sleep thought to be involved in maintenance of circadian rhythm and normal sleep-wake cycle.

Dosing

Adult

8 mg PO 30 min before bedtime on empty stomach

Pediatric

Not established

Interactions

Major substrate of cytochrome P450 CYP1A2 and minor substrate of CYP2C and CYP3A4; strong CYP1A2 inhibitors (eg, fluvoxamine) increase AUC up to 190-fold and C_max 70-fold; strong CYP inducers (eg, rifampin) decrease total exposure by mean of 80%; strong CYP3A4 inhibitors (eg, ketoconazole) and strong CYP2C9 inhibitors (eg, fluconazole) may increase serum levels

Contraindications

Documented hypersensitivity; strong cytochrome P450 CYP1A2 inhibitors (eg, fluvoxamine); severe hepatic impairment

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with mild hepatic impairment; adverse effects leading to discontinuation in clinical trials included dizziness, nausea, fatigue, headache, and worsening insomnia

Follow-up

Further Inpatient Care

Inpatient care is not usually required unless significant medical or psychiatric comorbidity exists.

Further Outpatient Care

Effective treatment for insomnia consists of a dual approach using nonpharmacologic techniques and appropriate use of hypnotic agents.

Patients need to be observed closely and have regular follow-up visits to review response, adverse effects, and to assure safe and appropriate use of the medications.

Deterrence/Prevention

Proper attention to sleep hygiene may prevent the development of psychophysiological insomnia.

Complications

Sleep disturbance is a reliable indicator of psychological ill health, physical ill health, or both. A report of disturbed sleep from the patient signals the need for further evaluation and close monitoring.

Prognosis

In some patients, improvement in sleep leads to an improved quality of life.

Patient Education

• The following sleep hygiene recommendations that include environmental and lifestyle modifications should be used as an adjunct to other forms of therapy.
  • Eliminate the use of caffeine, especially after noon.
  • Do not use tobacco or alcohol near bedtime.
  • Avoid heavy meals close to bedtime (may eat a light snack at bedtime).
  • Exercise early in the day before dinner to alleviate stress, but do not exercise before bedtime.
  • Avoid daytime naps, and establish a regular schedule for going to bed and getting up.
  • Keep the bedroom at a comfortable temperature, and minimize light and noise.
• Family education and patient self-help information are also important. Resources on sleep disorders can be found at the National Sleep Foundation Web site. For education on various disorders, patients can be directed to the Web sites of the Patient Education Institute, NIH Senior Health, and the United States Department of Health and Human Services.
• For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center and Sleep Disorders Center. Also, see eMedicine's patient education articles Primary Insomnia, Insomnia, Disorders That Disrupt Sleep (Parasomnias), Understanding Insomnia Medications, Sleep Disorders in Women, Sleep Disorders and Aging, Sleeplessness and Circadian Rhythm Disorder.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose

Multimedia

Media file 1: Primary insomnia. Evaluation of insomnia. Format of sleep diary.

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Keywords

sleeplessness, sleep disturbance, sleep apnea, psychophysiological insomnia, learned insomnia, behavioral insomnia, idiopathic insomnia, stress-related insomnia, sleep state misperception, persistent psychophysiological insomnia, sleep disorder

Contributor Information and Disclosures

Author

Catherine McVearry Kelso, MD,, Assistant Professor of Internal Medicine, Virginia Commonwealth University; Medical Director, Hospice and Palliative Care, Hunter Holmes McGuire VA Medical Center, Richmond
Catherine McVearry Kelso, MD, is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Geriatrics Society, and American Society for Bioethics and Humanities
Disclosure: Nothing to disclose.

Coauthor(s)

Angela Gentili, MD, Director of Geriatrics Fellowship Program, Associate Professor, Department of Internal Medicine, Virginia Commonwealth University Health System and McGuire Veterans Affairs Medical Center
Angela Gentili, MD is a member of the following medical societies: American Geriatrics Society
Disclosure: Nothing to disclose.

Antony Fernandez, MD, FRCPsych (UK), Associate Professor, Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University; Acting Director, Sleep Disorders Clinic, McGuire Veterans Affairs Medical Center, Richmond
Antony Fernandez, MD, FRCPsych (UK) is a member of the following medical societies: American Society of Addiction Medicine
Disclosure: Nothing to disclose.

Medical Editor

Jennifer S Morse, MD, Assistant Clinical Professor, Department of Psychiatry, University of California at San Diego
Jennifer S Morse, MD is a member of the following medical societies: Academy of Psychosomatic Medicine, Aerospace Medical Association, and American Psychiatric Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Iqbal Ahmed, MBBS, Professor, Department of Psychiatry, John A Burns School of Medicine, University of Hawaii
Iqbal Ahmed, MBBS is a member of the following medical societies: Academy of Psychosomatic Medicine, American Association for Geriatric Psychiatry, American Neuropsychiatric Association, and American Psychiatric Association
Disclosure: Nothing to disclose.

CME Editor

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin
Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: lilly Honoraria Speaking and teaching; Forest Labs Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; Pfizer Grant/research funds Speaking and teaching; Northstar Grant/research funds Research; Novartis Grant/research funds research; Pfizer  Speaking and teaching; Sanofi-avetis Grant/research funds research; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research

Chief Editor

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Stephen Soreff, MD is a member of the following medical societies: American College of Mental Health Administration and American Psychosomatic Society
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Aparna Ranjan, MD and Kirk L Nelson, MD to the development and writing of this article.

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