Insomnia and Sleep Disorders Notes

Initiating Drug Therapy

• Nonpharmacologic therapy should be tried first, addressing key causes with appropriate interventions:

  • Counseling

  • Behavioral management

  • Lifestyle alterations for psychiatric problems

• Insomnia often co-occurs with:

  • Major depression

  • Anxiety

  • Obsessive disorders

  • Dysthymic disorders

  • Psychotherapy should target the specific psychiatric disorder.

• Review proper sleep hygiene as an adjunct to drug therapy.

• Important lifestyle changes can enhance sleep; the importance of sleep hygiene should not be underestimated.

• Implement only one or two behavioral changes at a time.

• Follow-up and a strong patient-provider relationship are essential.

Goals of Drug Therapy

• Improve sleep quality and quantity.

• Improve insomnia-related daytime impairment.

• Drug selection should match the onset and duration to the sleep defect.

• All hypnotics promote sleep if given in adequate doses.

• Determine the minimal effective dose to minimize side effects.

• Factors in selecting a pharmacologic agent:

  1. Symptom pattern

  2. Treatment goals

  3. Past treatment responses

  4. Patient preference

  5. Cost

  6. Medication interactions

  7. Side effects

• Hypnotics are the primary drugs used for insomnia:

  • Benzodiazepines

  • Benzodiazepine receptor agonists

  • Melatonin receptor agonists

  • First-generation antihistamines

• Prescribe hypnotics for the shortest time possible.

• Short-term use: no more than 2 to 3 weeks, combined with behavioral interventions.

Recommended Order of Treatment for Insomnia

• First Line

  • Agents: Benzodiazepines (e.g., alprazolam, lorazepam, temazepam), benzodiazepine receptor agonists (BZRAs) (zolpidem, zaleplon, escitalopram), or ramelteon

  • Comments:

    • Agent selected should match the sleep deficit.

    • For pregnant women, consider Category A agents.

    • Consider short-acting agents, especially with patients who have renal or hepatic problems.

    • Consider antidepressant with comorbid depression

• Second Line

  • Agents: First-generation antihistamine-doxylamine succinate

• Third Line

  • Agents:

    • Alternating short-acting BZRAs (zaleplon, eszopiclone) with ramelteon

    • Sedating antidepressants (trazodone, amitriptyline, doxepin, mirtazapine)

    • Sedating antiepilepsy agents (gabapentin) or atypical antipsychotics (quetiapine, olanzapine)

    • Orexin receptor antagonist (suvorexant)

First-Line Therapy

• Key: Identify the sleep defect and match the agent to the classification of insomnia and the altered aspect of sleep.

• Recommended first-line therapy for short-term insomnia: benzodiazepines, benzodiazepine receptor agonists, or ramelteon.

  • Examples: zolpidem, eszopiclone, zaleplon, and temazepam.

• Doxylamine succinate is the only agent designated as pregnancy category A for treating any sleep defect in pregnant women.

• Assess the potential side effects and benefits for both the fetus and mother before starting therapy.

Second-Line Therapy

• If therapy is unsuccessful (lack of improvement in treatment goals), alternate short-acting BZRAs or ramelteon.

• If the patient has a comorbid condition such as depression, consider sedating antidepressants such as trazodone, amitriptyline, doxepin, and mirtazapine.

• These agents may be helpful, especially with patients who have anxiety.

• Consider the type of sleep defect and select a drug with the appropriate onset and half-life.

Third-Line Therapy

• Consider various combinations of therapy based on lack of goal achievement.

• Reassess the insomnia situation for patients who fail to respond to first- and second-line therapies.

• Chronic insomnia benefits most from continual evaluation and behavioral therapy.

• Consider other sedating agents in the antiepilepsy class, such as gabapentin, and atypical antipsychotics, including quetiapine and olanzapine.

Benzodiazepine Receptor Agonists vs. Benzodiazepines

• Benzodiazepine receptor agonists (BZRAs) are pharmacologically similar to benzodiazepines but mimic the action of GABA, an inhibitory transmitter that induces sleepiness.

• The difference between BZDs and BZRAs is which GABA-A receptor subunits are affected.

• BZDs act on the alpha-1, alpha-2, and alpha-3 subunits, while BZRAs are selective for alpha-1, which induces sleepiness but not anxiolysis or muscle relaxation.

• Complex sleep-related behaviors (activities in an altered state of consciousness) have been reported with BZRAs.

  • Examples: sleepwalking, eating, and driving a car.

• Other side effects of this class:

  • Decreased motor coordination

  • Confusion

  • Anterograde amnesia (thought to be less than with BZDs)

Eszopiclone (Lunesta)

• A benzodiazepine receptor agonist indicated for the treatment of insomnia.

• Dosage:

  • Nonelderly adults: start at 2 mg immediately before bed; may increase to 3 mg for sleep maintenance.

  • Elderly patients: start at 1 mg to help fall asleep; may increase to 2 mg if sleep maintenance is the issue.

• Limited use of the 3-mg dose is recommended due to impairment of driving ability, coordination, and memory for over 11 hours.

• Onset of action is rapid, with a peak plasma concentration occurring within 1 hour of dosing.

• Peak concentration can be delayed if taken with or shortly after a high-fat meal.

Zolpidem

• Zolpidem tartrate (Ambien), extended-release zolpidem tartrate (Ambien CR), sublingual zolpidem tartrate (Intermezzo), and zolpidem tartrate oral solution (Zolpimist) are also benzodiazepine receptor agonist products.

• Dosage:

  • Starting doses are lower for females than males.

    • Zolpidem: 5 mg for females, 10 mg for males.

    • Extended-release zolpidem: 6.25 mg for females, 12.5 mg for males.

    • Dosing can be increased, but this increases the potential for side effects.

  • Dosing should be altered for patients with hepatic impairment but is not necessary for those who are renally impaired.

• Time Frame for Response:

  • Onset of action: 10 to 15 minutes; lasts for 2 to 3 hours.

  • Extended-release zolpidem: 60% is initially released, with the remaining over the next 6 to 8 hours.

  • Sublingual and oral solution products: taken immediately prior to bedtime due to rapid onset of action.

Zaleplon

• Another benzodiazepine receptor agonist, chemically unrelated to benzodiazepines, barbiturates, and other drugs with hypnotic properties.

• Dosage:

  • Dose should be individualized and can range from 5 to 20 mg.

  • The risk of adverse effects is dose-dependent.

• Time Frame for Response:

  • Onset of action is rapid, within 1 hour after oral administration.

  • Short half-life of 1 hour.

  • Can be taken as little as 5 hours before the scheduled wake-up time, with no lingering effects of daytime sedation.

Orexin Receptor Antagonists

• A new class in the treatment of insomnia.

• The only agent in the class is suvorexant (Belsomra).

• Orexin neuropeptides (orexin-A and orexin-B) are found in the hypothalamus and other areas of the brain and perform a role in arousal, appetite, metabolism, reward, stress, and autonomic function.

• Dosage:

  • Starting dose: 10 mg; can be increased to a maximum of 20 mg.

  • Administration should occur within 30 minutes of bedtime.

  • Patients need to have at least 7 hours of planned sleep due to potential complex sleep behaviors.

  • Dose adjustment for hepatic and renal impairment is not required.

• Time Frame for Response:

  • Onset of action occurs within 30 minutes of administration with peak concentrations in 2 hours.

  • Suvorexant can last up to 6 hours.

Melatonin Receptor Agonists

• Ramelteon (Rozerem) was introduced as an option to treat insomnia in 2005.

• Endogenous melatonin is secreted from the pineal gland and regulates the circadian sleep cycle; ramelteon is a synthetic derivative.

• It does not affect other sleep neurotransmitters such as GABA, dopamine, or serotonin.

• Dosage:

  • The dose is 8 mg and should be administered within 30 minutes of going to bed.

  • Avoid administration with a high-fat meal.

• Time Frame for Response:

  • Onset of action is within 45 minutes, and the half-life is 1 to 2.6 hours.

  • There are no accumulating effects with repeated use due to the short half-life.

  • Administration with a high-fat meal can increase the area under the curve (total exposure).

Antihistamines

• One of the most commonly used classes of OTC sleep-inducing agents.

• Often come in combination with analgesics such as acetaminophen and ibuprofen.

• One of the most commonly used agents is diphenhydramine (Benadryl).

  • The main mechanism is to competitively inhibit histamine at the H1 receptor with substantial sedative and anticholinergic effects.

• No scientific evidence exists in the literature supporting the use of diphenhydramine to relieve insomnia or prolong sleep.

• Side effects of diphenhydramine include excessive daytime drowsiness, impaired psychomotor function, and increasing tolerance to the drug.

• Another first-generation antihistamine agent used for insomnia is doxylamine succinate (Unisom).

• Precautions include excessive drowsiness, which can affect coordination, therefore impairing psychomotor coordination.

Antidepressants

• Also may be used in the treatment of insomnia, but only for patients with comorbid depression.

• The most commonly used antidepressants in this category are mirtazapine (Remeron), trazodone, and doxepin (Silenor).

• If the patient has comorbid panic or anxiety, some newer agents may assist with sleep.

  • Example: trazodone, which also has some sedating as well as antianxiety effects.

Insomnia Treatment Algorithm

• Step 1: Presenting complaint: insomnia symptoms

• Step 2: Analyze duration and category of sleep defect (latency, maintenance, combination)

• Step 3: Look for underlying causes: medical, psychological, medications

• Step 4: Assess sleep hygiene with sleep diary

• Step 5: Initiate behavioral therapy. If effective after 2 weeks continue behavioral therapy, if not consider drug therapy.

• Implement short-term use of appropriate agent:

• Latency: rapid onset BZD or BZRA or ramelteon

• Maintenance: moderate to long duration BZD or BZRA

• Comorbid depression or anxiety: strongly consider antidepressant a sedating

• Step 6: Monitor over the short term. If effective after 2 weeks, continue. If not reevaluate appropriateness of selected agent.

• Step 7: Consider referral to specialist especially for excessive daytime sleepiness or chronic insomnia

Case Study

• S.H., age 47, reports difficulty falling asleep and staying asleep.

• Problems have been ongoing for many years.

• Self-treated with OTC Tylenol PM.

• Experiencing perimenopausal symptoms of night sweats and mood swings.

• Current medical problems include hypertension controlled with medications.

• Past medical history includes childhood illnesses of measles, chickenpox, and mumps.

• Family history is positive for diabetes on the maternal side and hypertension on the paternal side.

• Her only medication is an angiotensin-converting enzyme inhibitor and diuretic combination for hypertension control.

• She generally does not like taking medication and does not take any other OTC products.

Case Study Questions

1. List specific goals of therapy for S.H.

2. What drug therapy would you prescribe? Why?

3. Discuss specific patient education based on the prescribed therapy.

4. List one or two adverse reactions for the selected agent that would cause you to change therapy.

5. What would be the choice for second-line therapy?

6. What OTC and/or alternative medicines might be appropriate for this patient?

7. What dietary and lifestyle changes might you recommend?