What are the FDA-approved medications for treating sleep disturbances in patients?

FDA-Approved Sleep Medications

The FDA has approved 10 medications for insomnia treatment, including benzodiazepines (e.g., temazepam), nonbenzodiazepines/Z-drugs (zolpidem, eszopiclone, zaleplon), ramelteon (melatonin receptor agonist), and suvorexant (orexin receptor antagonist), with selection based on matching drug characteristics to specific sleep complaints and starting at the lowest available dose. 1

FDA-Approved Medication Classes

Benzodiazepine Receptor Agonists (BzRAs)

• Short-intermediate acting benzodiazepines are FDA-approved for insomnia, with temazepam being a commonly used example 1
• These medications have hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant, and amnestic properties 1
• The NIH State-of-Science Conference concluded that benzodiazepine receptor agonists are efficacious for short-term insomnia management 1

Nonbenzodiazepines (Z-drugs)

• Zolpidem is FDA-approved with recommended doses of 5 mg for immediate-release and 6.25 mg for extended-release formulations (reduced from previous higher doses due to next-morning impairment risk) 1, 2
• Eszopiclone is FDA-approved for both sleep-onset and maintenance insomnia with no short-term usage restriction 3
• Zaleplon is FDA-approved as another nonbenzodiazepine option 1
• These agents are structurally unrelated to benzodiazepines but have similar mechanisms of action with potentially lower frequency and severity of adverse effects compared to older benzodiazepines 1

Melatonin Receptor Agonist

• Ramelteon (8 mg) is FDA-approved and acts on melatonin receptors involved in maintaining circadian rhythm underlying the sleep-wake cycle 1, 3, 4
• This medication has shown no significant effects indicative of abuse potential or motor and cognitive impairment 1
• Ramelteon has no abuse potential or dependence risk but is primarily effective for sleep-onset rather than maintenance insomnia 3

Orexin Receptor Antagonist

• Suvorexant (10-20 mg) is FDA-approved for treatment-resistant insomnia, particularly for sleep maintenance, with a favorable side effect profile 5

Recommended Treatment Sequence

First-Line Pharmacologic Approach

For primary insomnia, the recommended sequence when pharmacotherapy is utilized is: 1

1. Short-intermediate acting BzRAs (zolpidem, eszopiclone, zaleplon, temazepam) or ramelteon
2. Alternate short-intermediate acting BzRAs or ramelteon if initial agent unsuccessful
3. Sedating antidepressants (especially with comorbid depression/anxiety): trazodone, amitriptyline, doxepin, mirtazapine
4. Combined BzRA or ramelteon with sedating antidepressant
5. Other sedating agents for comorbid conditions: anti-epilepsy medications (gabapentin, tiagabine) or atypical antipsychotics (quetiapine, olanzapine)

Special Population Considerations

Elderly Patients:

• The American Geriatrics Society recommends melatonin receptor agonists as first choice for pharmacological treatment, starting at the lowest available dose 6
• Short-acting non-benzodiazepines can be used as second choice, but caution is advised due to next-morning psychomotor and memory impairment risk 6
• Short-acting benzodiazepines should be used with extreme caution, requiring 50% dose reduction from standard adult doses with close monitoring for respiratory depression, confusion, and fall risk 6
• Benzodiazepines should be avoided in older patients and those with cognitive impairment due to decreased cognitive performance 1

Cancer/Palliative Care Patients:

• For refractory insomnia: lorazepam (short-acting benzodiazepine), zolpidem (nonbenzodiazepine), antipsychotics (chlorpromazine, quetiapine, olanzapine), or sedating antidepressants (trazodone, mirtazapine) 1
• Mirtazapine may be especially effective in patients with depression and anorexia 1

Critical Safety Warnings

Complex Sleep Behaviors

• Zolpidem carries an FDA black box-level warning for complex sleep behaviors including sleep-walking, sleep-driving, and engaging in activities while not fully awake, which may occur after first or any subsequent use 2
• These behaviors can result in serious injury or fatal outcomes 2
• Discontinue zolpidem immediately if complex sleep behavior occurs 2

Next-Day Impairment

• The risk of next-day psychomotor impairment is increased if zolpidem is taken with less than 7-8 hours of sleep remaining, at higher than recommended doses, or with other CNS depressants 2
• The FDA required lower zolpidem doses (5 mg immediate-release, 6.25 mg extended-release) specifically due to next-morning impairment risk 1

Drug Interactions

• Coadministration with other CNS depressants (benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases CNS depression risk and requires dosage adjustments 2

Medications NOT Recommended

The following are explicitly not FDA-approved or not recommended for chronic insomnia: 1

• Over-the-counter antihistamines or antihistamine/analgesic combinations due to lack of efficacy and safety data 1, 3
• Herbal and nutritional substances (valerian, melatonin supplements) due to relative lack of efficacy and safety data 1
• Older drugs including barbiturates, barbiturate-type drugs, and chloral hydrate 1

Essential Clinical Practice Requirements

Patient Education

All pharmacological treatment must be accompanied by education regarding: 1

• Treatment goals and expectations
• Safety concerns
• Potential side effects and drug interactions
• Other treatment modalities (cognitive and behavioral treatments)
• Potential for dosage escalation
• Rebound insomnia

Monitoring Requirements

• Patients should be followed every few weeks initially to assess effectiveness, side effects, and need for ongoing medication 1
• For elderly patients on any sleep medication, monitor for respiratory depression, confusion/delirium, falls and fractures, next-day cognitive impairment, and worsening dementia symptoms 6

Duration Considerations

• Most FDA approvals focus on short-term use, though eszopiclone has no short-term usage restriction 3
• Failure of insomnia to remit after 7-10 days may indicate primary psychiatric/medical illness requiring evaluation 2