Insomnia

Background

Insomnia is a common accompaniment to HIV infection, especially as the disease progresses and complications worsen. Once present, insomnia tends to be chronic, unlike the transient disturbances of sleep that are a normal part of life. Most insomnia related to HIV can be characterized by the amount, quality, or timing of sleep. Insomnia may cause progressive fatigue and diminished functioning.

S: Subjective

The patient may complain of the following:

  • Difficulty initiating sleep
  • Early-morning awakening
  • Mind-racing thoughts (e.g., "I can't turn off my thoughts.")
  • Difficulty maintaining sleep
  • Nonrestorative sleep (i.e., although the amount of sleep is adequate, the patient does not feel rested upon awakening)
  • Nighttime restlessness

Ask about the symptoms above, and about the following:

  • Determine the patient's bedtime sleep habits; request additional history from a sleep partner, if possible
  • Try to quantify how long the patient actually sleeps each night

Ask about the following:

  • Alcohol and recreational drug use
  • Caffeine intake (quantity, times of day)
  • Nightmares, life stressors
  • Concurrent medications that may cause insomnia as an adverse effect (e.g., efavirenz, corticosteroids, pseudoephedrine, and decongestants)
  • Medications (prescription or over-the-counter) or supplements used to promote sleep
  • Shift work, exercise, nighttime reflux or heartburn, snoring, and periods of apnea (not breathing)
  • Collar size (size >16 more often associated with sleep apnea)

Screen for depression and anxiety.

O: Objective

Perform a general symptom-directed physical examination, including evaluation of body habitus, neurologic status, and mental status.

A: Assessment

A partial differential diagnosis includes the following:

  • Alcohol intake (interferes with sleep 2-4 hours after ingestion, may cause nocturnal awakening)
  • Caffeine intake
  • Recreational drug use
  • Anxiety disorder
  • Major depression (insomnia is a primary symptom)
  • Transient insomnia related to acute stress
  • Cognitive impairment
  • Disturbance of the sleep/wake cycle because of excessive time in bed or inadequate sleep hygiene (e.g., noise in the bedroom)
  • Medication adverse effects (e.g., from steroids, efavirenz)
  • Other identifiable sleep disorders (e.g., obstructive sleep apnea, periodic leg movements)
  • Pain
  • Underlying systemic medical conditions that can interfere with sleep, such as delirium, lung disease, congestive heart failure, renal failure, diarrhea, and incontinence

P: Plan

Evaluation

The diagnosis usually is based on history. A sleep evaluation (including polysomnography) may be indicated when a physiologic cause (e.g., obstructive sleep apnea) is suspected or insomnia is severe.

Treatment

Treat underlying illnesses that may be causing or contributing to insomnia.

  • Manage correctible medical conditions that may interfere with sleep.
  • Treat depression and anxiety disorders. These are very common contributors to insomnia among people with HIV infection. See chapters Major Depression and Other Depressive Disorders, Anxiety Disorders, and Panic Disorder.
  • If the patient is suspected of having sleep apnea, periodic limb movements in sleep, or restless limb syndrome, refer to a specialist in sleep medicine for evaluation.

The following options are available for treatment:

Behavioral strategies

  • To correct deleterious sleep habits, patients should do the following:
    • Establish a bedtime routine.
    • Avoid stimuli before bedtime.
    • Avoid vigorous exercise within 3-4 hours of bedtime.
    • Reduce or eliminate daytime napping.
    • Avoid eating, reading, watching TV, or working in bed.
    • Wake up at the same time each day regardless of total hours of sleep.
    • Have a dark, cool, quiet, comfortable environment conducive to sleep.
    • Place the bedroom clock out of sight.
  • If unable to fall sleep after 15-20 minutes, the patient should get up, go into another room for nonstimulating activity in dim light (such as reading), and not go back to bed until sleepy.
  • The patient should discontinue use of caffeine, central nervous system stimulants, alcohol, and tobacco, with tapering if necessary, to avoid withdrawal symptoms.
  • Teach or refer the patient for relaxation techniques.

Pharmacotherapy

Choosing a pharmacologic agent for insomnia

A number of medications may be effective in treating insomnia. In selecting a medication for an individual patient, consider the following about a specific medication:

  • Is it likely to improve symptoms that may be contributing to the patient's insomnia (e.g., depression, anxiety, psychosis, neuropathic pain)?
  • Does it pose risks to the patient based on comorbid medical conditions (e.g., benzodiazepines should not be given to patients with sleep apnea, tricyclic antidepressants should not be given to patients with cardiac conduction problems)?
  • Does it have adverse interactions with other medications (e.g., zolpidem [Ambien], zaleplon [Sonata], and eszopiclone [Lunesta] should be used with caution in patients taking protease inhibitors [PIs])?
  • Is it the optimal agent for a patient with a current or past history of alcohol or sedative abuse/dependence?
  • Is it affordable (e.g., formulary or co-pay issues)?

Treatment considerations

There are limited data to guide the frequency (nightly, intermittently, as needed) and duration (brief, intermediate, long-term) of hypnotic medications. Hypnotics should be prescribed at the lowest effective dosage for the shortest possible period. The greater the degree of physical illness, the more likely the patient will need a low dosage of a hypnotic agent. When long-term treatment is necessary, benzodiazepines pose the greatest risk of tolerance, abuse, and dependence.

Possible adverse effects of all hypnotics include excess sedation, daytime grogginess, impaired judgment, behavior changes, and disruption of the sleep architecture. In addition, persons taking hypnotics may engage in overnight activities or behaviors without being fully awake, and may not remember these activities afterwards (e.g., walking, driving, eating); they also may have impairment in cognition and motor skills the next morning.

Interactions may occur between certain antiretrovirals (ARVs) and agents used to treat insomnia. Some combinations may be contraindicated and others may require dosage adjustment. Refer to medication interaction resources or consult with an HIV expert, psychiatrist, or pharmacist before prescribing.

Agents with FDA-Approved Indications for Insomnia

Antihistamines

  • The antihistamines diphenhydramine, doxylamine, and hydroxyzine, given at doses of 25-50 mg QHS, can be used for sleep. Adverse anticholinergic effects often interfere with long-term use.

Antidepressants

  • Trazodone, 25-50 mg; maximum dose: 200 mg QHS.
    • Trazodone, a triazolopyridine derivative antidepressant and sedative, is the only antidepressant with a U.S. Food and Drug Administration (FDA) indication for insomnia, and it is widely used for this purpose. However, levels may be increased by ritonavir-boosted PIs and by the pharmacokinetic booster cobicistat. Do not use with saquinavir/ritonavir; use lower dosages for patients receiving other PIs or cobicistat. Trazodone may (rarely) cause priapism. Trazodone can be used for an indefinite period of time as it is not associated with tolerance or addiction.

Non-benzodiazepine hypnotics (agonists of the benzodiazepine receptor)

  • Zolpidem (Ambien) 5 mg for women, 5-10 mg for men, 5 mg for geriatric patients; zolpidem-CR (Ambien-CR) 6.25 mg for women, 6.25-12.5 mg for men; zaleplon (Sonata) 5-10 mg; and eszopiclone (Lunesta) 2-3 mg QHS.
    • These newer hypnotic agents are benzodiazepine receptor agonists with shorter half-lives than benzodiazepines and may be less likely to result in day-after drowsiness. They may have decreased addiction potential compared with benzodiazepine hypnotics. Higher doses and extended-release formulations appear to increase the risk of next-morning impairment. Patients should be advised to use these hypnotics on an as-needed basis rather than nightly; it is easier for patients to discontinue a drug that they are not taking every day. The inhibition of CYP 3A4 enzyme activity by PIs or cobicistat may increase levels of these benzodiazepine receptor agonists, particularly eszopiclone; this may cause excessive sedation or respiratory depression.

Melatonin agonists

  • Ramelteon (Rozerem), 8 mg QHS.
    • The first of a new class of melatonin agonists to receive FDA approval, ramelteon may have some advantages over sedative/hypnotic agents, such as reduced dependence and overuse. However, it may have severe adverse reactions, including hypersensitivity reactions such as anaphylaxis and angioedema. Long-term interactions with ARV agents are unknown.

Benzodiazepine hypnotics

  • A number of benzodiazepines have FDA-approved indications for the short-term treatment of insomnia. They carry a risk of addiction and residual drowsiness the following day.
  • Metabolized by glucuronidation; predicted to have few drug interactions with ARVs:
    • Temazepam (Restoril) 7.5-30 mg; intermediate half-life
    • Lorazepam (Ativan), 1-2 mg; intermediate half-life.
  • Metabolized by CYP 34A; PIs and cobicistat may prolong their duration, resulting in excessive daytime somnolence. These may be most beneficial for use with patients whose insomnia is associated with anxiety:
    • Flurazepam (Dalmane) 15-30 mg
    • Quazepam (Doral) 7.5-15 mg
    • Estazolam (ProSom) 1-2 mg
  • Clonazepam (Klonopin) at a dose of 0.5-2 mg has been approved for treatment of periodic leg movements. PIs and cobicistat may prolong its duration and increase risk of adverse effects; start at low dosage and titrate slowly.
  • Triazolam (Halcion), another approved agent for insomnia, is contraindicated for use with all PIs, some nonnucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz), and cobicistat because of potentially life-threatening reactions (e.g., respiratory depression)

Agents Used for Sedating Side Effects (no FDA indication for insomnia)

Antidepressants

  • Tricyclic antidepressants at doses of 10-50 mg can be beneficial for sleep, but they have longer half-lives than short-acting hypnotic agents, and potential adverse effects include cardiac dysrhythmias and pulmonary complications. Tricyclics generally should be avoided for geriatric patients. Levels of tricyclics are elevated by ritonavir and by cobicistat, and lower dosages may be needed for patients taking ritonavir or ritonavir-boosted PIs or cobicistat. Routine testing of tricyclic blood levels should be performed on patients receiving higher doses (e.g., 100 mg per day; 50 mg for nortriptyline), those concurrently on ritonavir, and those with risk factors for cardiac conduction abnormalities. A routine electrocardiogram should be performed before prescribing tricyclics, and this class of drugs should not be prescribed to patients with cardiac conduction problems. However, tricyclic antidepressants also have characteristics that may benefit some patients, including treatment of chronic pain, promotion of weight gain, and reduction of diarrhea. Amitriptyline (Elavil) and doxepin (Sinequan) are the most sedating of the tricyclic antidepressants and therefore are the drugs in this class most often used for sleep.
  • The tetracyclic antidepressant mirtazapine (Remeron) is sedating and has been effective in treating insomnia at low dosages (7.5-15 mg). Higher dosages may result in increased activation owing to increased norepinephrine (NE) receptor antagonism.
  • The selective serotonin reuptake inhibitor (SSRI) antidepressants are not sufficiently sedating to be used as sleeping agents, but when insomnia is caused by depression, sleep will improve as the depression lifts.

Anticonvulsants

  • Gabapentin (Neurontin) can be useful for patients with insomnia and has been demonstrated to be particularly beneficial for patients with alcohol and other substance-use disorders; it is widely prescribed for neuropathic pain.

Patient Education

  • Instruct patients in behavioral interventions that can help to reduce insomnia.
  • Additional interventions are available when behavioral interventions are not sufficient.
  • Patients should be warned strongly about risks associated with medications used to treat insomnia, including the risk of sleepwalking and other overnight activities and next-morning impairment in cognition and coordination.
  • Patients should report new or worsening symptoms to their health care provider. These may be not only signs of worsening insomnia, but also of symptoms of anxiety, depression, medications, or changes in medical conditions

References

  • FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). January 10. 2013.
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  • Kuppermann M, Lubeck DP, Mazonson PD, et al. Sleep problems and their correlates in a working population. J Gen Intern Med. 1995 Jan;10(1):25-32.
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  • Sleep and Wakefulness Disorders. In: The Merck Manual of Diagnosis and Therapy, 18th ed. ; Beers MH, Porter RS, Jones TV, eds. Whitehouse Station, NJ: Merck & Co.; 2006:1834-40.
  • Wainberg ML, Faragon J, Cournos F, et al. Psychiatric Medications and HIV Antiretrovirals: A Guide to Interactions for Clinicians, 2nd ed. Laminated booklet produced by the New York/New Jersey AIDS Education and Training Center, Health Resources and Services Administration; 2008.