Resident Editor: Brian Secemsky, MD

Faculty Editor: Doug Bauer, MD

BOTTOM LINE ✔ Exclude secondary causes (OSA, pain, restless leg syndrome, etc), medication-related and substance use. ✔ Treat first with sleep hygiene and CBT. ✔ Use pharmacologic agents as last resort or in combination with CBT.

Background/Epidemiology

• Insomnia is difficulty falling asleep (sleep latency), difficulty staying asleep or poor sleep quality that impairs daytime functioning despite adequate circumstances for sleep
• Insomnia disorder is a risk factor for coronary artery disease, depression and metabolic syndrome, though unclear if treatment of insomnia modifies this risk
• Lifetime occurrence of symptoms in US is 35-50%, whereas the prevalence of insomnia disorder is 12-20%
• 10-15% of individuals suffer distress or functional impairment related to insomnia that impacts their health and well-being

Risk Factors

• Depression, female sex, older age, African American, lower SES
• Concurrent medical and mental disorders, including drug/alcohol use
• Marital status (greater risk in divorced/separated)
• Family history of insomnia disorder

Differential Diagnosis of Acute and Chronic Insomnia

Acute insomnia (less than 3 weeks): change in sleep environments, jet lag, changes in work shift, stressful life events, acute medical illness, stimulant medications (theophylline, beta blockers, steroids, levothyroxine, bronchodilators), withdrawal of depressant meds – including EtOH

• Chronic insomnia (longer than 3 weeks):
  • poor sleep hygiene
  • psychophysiologic (maladaptive response in which bedtime is associated with heightened arousal)
  • sleep state misperception (mismatch between perception of sleep and objective findings),
  • Other: chronic illicit drug/alcohol use, underlying medical (COPD, CHF, hypothyroid, reflux, arthritis)/neurologic (stroke, migraine)/psychiatric disease (depression, bipolar, anxiety), medication side effects (antidepressants, antihypertensives, steroids, decongestants)
• Other sleep disorders that should be excluded: OSA, restless leg syndrome, narcolepsy, periodic limb movement disorder, REM sleep behavior disorder, circadian rhythm disorders
• DSM 5 removed distinction between “primary” and “secondary” causes of insomnia due to evidence that relationship between insomnia and other disorders (eg: depression) is bidirectional and directly treating insomnia can be helpful

Evaluation

• Medical/psychiatric history and physical exam to identify comorbid conditions
  • Assess for obstructive sleep apnea (OSA), pain, GERD, hot flashes, nocturnal cough, PTSD, restless leg syndrome, depression
• Look for medications that may affect sleep
  • Alpha- and beta-blockers, steroids, decongestants, narcotics
• Look for substance use
• Look for evidence of impaired daytime functioning
  • Fatigue, irritability, trouble concentrating, poor memory, etc.
  • Excessive daytime sleepiness (Epworth Sleepiness Scale score >10) raises concern for another sleep disorder, particularly OSA.
• Assess for behavioral and environmental factors (see Sleep Hygiene)
• When possible, interview the bed partner re: snoring, apnea, limb movements
• Consider having the patient record a sleep log (bed time, awakening time, naps, number of awakenings, and subjective evaluation of sleep quality)
• Polysomnography is not a recommended diagnostic tool for insomnia unless it is to evaluate for other sleep disorders like OSA, periodic limb movement disorder or narcolepsy OR if you have high suspicion for sleep state misperception

Treatment

• First address medical and psychiatric disease that affects sleep habits
• Universal sleep hygiene recommendations
  • Reduce environmental disruption 
    • TV and radio off
    • Pets outside the bedroom
    • Keep the room dark and quiet
    • Ear plugs or white noise if needed
  • Prevent circadian shifts
    • Set a regular wake time regardless of sleep duration
    • Avoid napping
  • Avoid alcohol, nicotine, caffeine, and large meals at night
  • Exercise regularly during the daytime

Cognitive behavioral therapy-insomnia specific (CBTi)                                      

• Highly evidence-based and very effective.  Undisputed first line therapy for insomnia with lasting results
• Traditionally 4-8 in person sessions with therapist
• Results are similar with phone, internet (SHUTi, Sleepio, Sleepstation) and book based therapies – variety of prices, largely restricted to English
• CBTi components we can use in Primary Care
  • Behavioral therapy
    • Stimulus control: make the bed a cue for sleep
      • Use the bedroom for sleep and sex only: no TV, radio, etc.
      • Go to bed only when tired
      • When unable to fall asleep in 15-20 minutes, go to another room
        • Engage in a quiet activity: reading
        • Return to bed only when sleepy
    • Sleep restriction: a structured plan to improve sleep efficiency
  • Cognitive therapy:
    • Correct unrealistic expectations: for example, that a minimum of 8 hours of sleep is required for health
    • Address anxiety and catastrophic thinking: for example, exaggerating to oneself the consequences of poor sleep

Pharmacologic therapy

• Successful pharmacologic therapy can improve quality of life and daytime functioning in patients that do not respond to CBT.
• Hypnotic agents approved by FDA for both primary and secondary insomnia disorders include: benzodiazepine receptor agonists (includes benzodiazepine and “non-benzodiazepine” agents), anti-histamines, TCAs, melatonin receptor agonists, and orexin receptor antagonists.
• Barbiturates are approved but are not recommended.

• Little data exists to support long-term therapy with pharmacologic agents.
• Common adverse effects include habituation, tolerance, dependence (rebound insomnia), and daytime sleepiness.
• All patients should be warned about the risks of sedative/hypnotics
  • Nocturnal falls
  • Impairment of activities that require mental alertness the morning after use, including driving, even when patients feel fully awake
  • Severe CNS depression when combined with alcohol or other drugs

Low risk, demonstrated benefits:

1. Melatonin agonists (ramelteon)
   • Ramelteon is a melatonin agonist that appears to decrease sleep onset latency and increase total sleep time
   • It is not associated with hypnotic side effects, withdrawal, or rebound insomnia
   • Most common adverse effects are nausea, headache, and sore throat
   • May cause reproductive hormonal dysregulation (e.g. decreased libido, delayed menses) by increasing prolactin and decreasing testosterone levels
2. Orexin Antagonists (suvorexant)

• Reversible antagonist competing with orexin neuropeptides from hypothalamus that promote wakefulness – improves sleep induction and maintenance
• Approved by FDA in 2014 for doses 5-20mg
• Metabolized by CYP3A4 system and dose should be reduced if pt also taking CYP3A4 inhibitors
• Most common adverse effects are somnolence, fatigue, headache, dry mouth

Low to moderate risk, not FDA approved for insomnia:

3. Antidepressants (trazodone, doxepin, mirtazapine)

• Trazodone and doxepin are thought to be sedating due to antihistaminergic activity (+alpha-adrenergic blockade for trazodone)
• Doxepin is only one FDA approved for insomnia at dose of 3-6mg – low risk of side effects at this dose, even in elderly
• Trazodone use is controversial between different recommendations – biggest risk is orthostatic hypotension (insomnia dose 25-100mg thought by most societies to be safe)
• Mirtazapine generally not recommended for insomnia disorder – can help sleep in patients with depression/anxiety

Higher risks, proven benefits:

4. Benzodiazepines (temazepam, estazolam, triazolam)

• GABA type A receptor agonists
• Clinical benefits
  • Decrease sleep latency and number of awakenings
  • Improve sleep duration and quality
  • Also decrease anxiety and impair memory
• Adverse effects
  • Daytime somnolence, cognitive impairment, and rapid tolerance and dependence are common
  • Long-term use is habit forming and rebound insomnia and withdrawal may occur when benzodiazepines are discontinued
  • Paradoxical agitation, delirium, and falls, especially in elderly patients
• Relative contraindications
  • Alcohol and/or sedative abuse/dependence
  • Severe pulmonary failure or untreated OSA
  • Hepatic failure
• Primary difference between agents is duration of effect

5. Nonbenzodiazepines (eszopiclone, zolpidem, zaleplon)

• More specific agonists of GABA type A receptor
• Clinical benefits
  • Decrease sleep latency and number of awakenings
  • Improve sleep duration and sleep quality
  • Less anxiolytic and anticonvulsant effect than benzodiazepines
  • Less dependence and rebound insomnia than benzodiazepines
  • Benefits primarily demonstrated in short-term therapy (up to seven days) although zolpidem and eszopiclone have shown benefit at up to six months
• Adverse effects
  • Similar to benzodiazepines
  • Daytime somnolence and cognitive impairment
  • Complex sleep-related behaviors and hallucinations
  • Paradoxical agitation and delirium, especially in elderly patients
• The FDA recommends decreased dose of zolpidem 5 mg in women

Generally not recommended:

6. Diphenhydramine

• Associated with daytime somnolence due to its long half-life
• Anticholinergic effects and paradoxical agitation, particularly in elderly patients

7. Other OTC medications (melatonin, valerian)

• Melatonin does not appear to have significant benefit for most patients with insomnia, however it is safe for short-term use up to three months
• Valerian is a common herbal medication that does not have efficacy in the treatment of insomnia and may produce hepatotoxicity

When to refer

• Most patients with chronic insomnia are treated by their primary care physicians
• Evaluation and treatment by a sleep specialist are appropriate when other sleep disorders are suspected (narcolepsy, apnea)

References

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Jaffer, Karim, et al. “Trazodone for Insomnia: A Systematic Review.” Innovations in Clinical Neuroscience, 2 Jan. 2018, innovationscns.com/trazodone-insomnia-july-august-2017/.

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Riemann, Dieter, et al. “European Guideline for the Diagnosis and Treatment of Insomnia.” Journal of Sleep Research, vol. 26, no. 6, 5 Sept. 2017, pp. 675–700., doi:10.1111.

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Schroeck, Jennifer L., et al. “Review of Safety and Efficacy of Sleep Medicines in Older Adults.” Clinical Therapeutics, vol. 38, no. 11, 2016, pp. 2340–2372., doi:10.1016/j.clinthera.2016.09.010.

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Srinivasan V, Brzezinski, A, Pandi-Perumal, SR, et al. "Melatonin agonists in primary insomnia and depression-associated insomnia: Are they superior to sedative-hypnotics?." Prog Neuropsychopharmacol Biol Psychiatry 2011;35(4):913-923

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