What are the guidelines for prescribing medications with a drowsy effect, such as benzodiazepines (BZD) and non-benzodiazepines, like zolpidem (Ambien) and eszopiclone (Lunesta), for conditions like insomnia and anxiety disorders?

Prescribing Medications with Drowsy Effects: Evidence-Based Guidelines

Cognitive Behavioral Therapy Must Come First

All adults with chronic insomnia should receive Cognitive Behavioral Therapy for Insomnia (CBT-I) as initial treatment before any pharmacological intervention, as it demonstrates superior long-term efficacy compared to medications with minimal risk of adverse effects 1, 2. CBT-I includes stimulus control therapy, sleep restriction therapy, relaxation techniques, and sleep hygiene education, though sleep hygiene alone is insufficient as monotherapy 1, 2.

First-Line Pharmacotherapy When CBT-I is Insufficient

For Sleep Onset Insomnia:

• Zolpidem 10 mg (5 mg in elderly) is recommended as first-line pharmacotherapy 2, with evidence showing 12-minute reduction in sleep onset latency 1
• Zaleplon 10 mg is an alternative for sleep onset difficulty 2
• Ramelteon 8 mg (melatonin receptor agonist) is recommended for sleep onset insomnia 2, particularly valuable as it lacks abuse potential and does not cause cognitive impairment 1

For Sleep Maintenance Insomnia:

• Low-dose doxepin 3-6 mg is the preferred first-line agent, especially in older adults 1, 2, reducing wake after sleep onset by 22-23 minutes 1
• Eszopiclone 2-3 mg is recommended for both sleep onset and maintenance 2, with evidence showing 28-57 minute increase in total sleep time and 17-minute reduction in wake after sleep onset 1, 3
• Temazepam 15 mg is an option for sleep maintenance 2, 4
• Suvorexant (orexin receptor antagonist) is recommended for sleep maintenance insomnia 2, reducing wake after sleep onset by 16-28 minutes 1

Critical Safety Warnings

FDA Black Box Warnings and Serious Risks:

• All nonbenzodiazepine hypnotics (zolpidem, eszopiclone, zaleplon) carry FDA warnings for serious injuries caused by complex sleep behaviors including sleep-driving, sleep-walking, and engaging in activities while not fully awake 1, 5, 6
• Patients must be counseled on these risks before prescribing, and medications should be used at the lowest effective dose for the shortest duration 1
• The morning after taking these medications, driving ability and cognitive function may be significantly impaired 5, 6
• Observational data indicates hypnotic drugs are associated with dementia (hazard ratio 2.34) 1

Specific Dosing Requirements:

• Women and elderly patients require lower doses: zolpidem maximum 5 mg in elderly, eszopiclone 1 mg in elderly or severe hepatic impairment 1, 2, 3
• Elderly patients face increased risks of falls, cognitive impairment, and complex sleep behaviors 1, 2

Medications to AVOID

Benzodiazepines Are Not Recommended:

Benzodiazepines should be avoided for insomnia treatment due to widely known harms that substantially outweigh benefits 1, including:

• High risk for dependency and diversion 1
• Falls and cognitive impairment, particularly in older patients 1
• Hypoventilation in patients with respiratory conditions including sleep apnea 1
• Tolerance, rebound insomnia, withdrawal symptoms, and abuse potential 7, 8
• If benzodiazepines must be used, they should be reserved as third-line agents only after first-line options have failed 2

Trazodone Should Be Avoided:

Trazodone is explicitly NOT recommended for treatment of chronic insomnia disorder 1, 3. The evidence shows:

• No differences in sleep efficiency or discontinuation rates compared to placebo 1
• No improvements in sleep onset latency, total sleep time, or wake after sleep onset 1, 3
• Low-quality evidence with adverse effects outweighing limited benefits 1, 3
• Consider trazodone only if treating comorbid major depression requiring full antidepressant dosing 3

Other Agents Not Recommended:

• Antihistamines (diphenhydramine) are not recommended due to lack of efficacy data and safety concerns including daytime sedation and delirium risk 1, 2
• Antipsychotics should not be used as first-line treatment 1, 2
• Herbal supplements (valerian) and melatonin supplements lack sufficient evidence 2

Treatment Duration and Monitoring

Short-Term Use is Essential:

• Pharmacotherapy should be prescribed at the lowest effective dose for the shortest possible duration, ideally less than 2-4 weeks 2, 4
• If insomnia persists beyond 7-10 days of treatment, evaluate for underlying sleep disorders such as sleep apnea or restless legs syndrome 2
• Regular monitoring is essential during initial treatment to assess effectiveness and side effects 2

Combination Therapy Warnings:

Never combine multiple sedative medications 3. Combining benzodiazepines, Z-drugs, or other sedatives significantly increases risks of:

• Excessive daytime sedation 3
• Impaired driving ability 3
• Falls and fractures 2
• Respiratory depression 3
• Complex sleep behaviors 2

Special Population Considerations

Elderly Patients (≥65 years):

• Require downward dose adjustments of all sedative-hypnotics 2
• Face increased sensitivity to peak drug effects and reduced drug clearance 1
• Higher risk for falls, cognitive impairment, and complex sleep behaviors 1, 2
• Doxepin 3-6 mg or controlled-release melatonin are recommended as first-line in older adults 1, 9

Patients with Respiratory Disease:

• Persons with sleep apnea or chronic lung disease with nocturnal hypoxia should be evaluated by a sleep specialist before prescribing any sedating medications 9
• Benzodiazepines are contraindicated due to hypoventilation risk 1

Patients with Comorbid Conditions:

• For comorbid depression/anxiety, consider sedating antidepressants (low-dose doxepin, mirtazapine) rather than benzodiazepines 2
• Patients with history of substance abuse should avoid benzodiazepines and consider ramelteon or suvorexant 2

Common Pitfalls to Avoid

• Prescribing benzodiazepines as first-line treatment instead of nonbenzodiazepine hypnotics 2
• Failing to implement CBT-I before or alongside pharmacotherapy 1, 2
• Using standard adult doses in elderly patients without downward adjustment 1, 2
• Continuing pharmacotherapy long-term without periodic reassessment 2
• Prescribing trazodone for insomnia when it lacks efficacy evidence 1, 3
• Combining multiple sedative agents, which exponentially increases adverse event risk 3
• Not counseling patients about complex sleep behaviors and next-day impairment 1, 5, 6
• Prescribing sedatives without screening for underlying sleep apnea 2, 9