eMedicine Specialties > Psychiatry > Adult

Primary Insomnia: Treatment & Medication

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
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; 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
Contributor Information and Disclosures

Updated: Jun 5, 2009

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

Open table in new window

* 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.

Quazepam (Doral)

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

Estazolam (ProSom)

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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