What can be prescribed for stress and sleep disorders?

Treatment for Stress and Sleep Disorders

Start with Cognitive Behavioral Therapy for Insomnia (CBT-I) as first-line treatment, and if pharmacotherapy is needed, prescribe zolpidem 5-10 mg or ramelteon 8 mg at bedtime, avoiding benzodiazepines entirely. 1, 2

First-Line Treatment: Non-Pharmacological Approach

CBT-I is the standard of care and should be offered before any medication. 1, 2 This multicomponent therapy includes:

• Stimulus control therapy: Use the bedroom only for sleep and sex, leave the bedroom if unable to sleep within 20 minutes 1
• Sleep restriction therapy: Limit time in bed to actual sleep time to achieve >85% sleep efficiency, with weekly adjustments 1, 3
• Cognitive therapy: Address maladaptive beliefs about sleep and anxiety-provoking thoughts 1
• Relaxation training: Progressive muscle relaxation, guided imagery, and diaphragmatic breathing 1, 3

Sleep hygiene alone is insufficient for chronic insomnia and must be combined with other CBT-I components. 1

Pharmacological Treatment Algorithm

When CBT-I fails, is unavailable, or the patient requires immediate symptom relief, follow this evidence-based sequence:

First-Line Medications

Benzodiazepine receptor agonists (BzRAs) or ramelteon are the recommended first-line pharmacotherapy: 1, 2

• Zolpidem 5-10 mg at bedtime (start with 5 mg in elderly, women, and those with hepatic impairment) for both sleep onset and maintenance insomnia 1, 2, 4
• Eszopiclone 1-3 mg at bedtime for patients with both sleep onset and maintenance difficulties 1, 2, 3
• Zaleplon 5-10 mg at bedtime specifically for sleep-onset insomnia due to ultra-short half-life 1, 2
• Ramelteon 8 mg at bedtime for sleep-onset insomnia, particularly suitable for patients with substance use history due to zero addiction potential 1, 2

Critical safety warnings for zolpidem: Patients must have 7-8 hours available for sleep to minimize next-day impairment and driving risk. 4 The risk of complex sleep behaviors (sleep-driving, sleep-walking) requires patient education. 4 Avoid in patients with severe hepatic impairment, sleep apnea, myasthenia gravis, or respiratory depression. 4

Second-Line Medications

If first-line agents fail, try an alternative BzRA or ramelteon before moving to other classes: 1

• Switch between zolpidem, eszopiclone, zaleplon, or ramelteon based on specific sleep complaint pattern 1

Third-Line Medications

Sedating antidepressants, particularly when comorbid depression or anxiety exists: 1, 2

• Low-dose doxepin 3-6 mg at bedtime for sleep maintenance insomnia with minimal anticholinergic effects 2, 3, 5
• Trazodone 25-100 mg at bedtime (though evidence is limited) 1
• Mirtazapine 7.5-30 mg at bedtime promotes sleep and appetite, useful for patients with weight loss 5
• Nortriptyline 10-40 mg at bedtime for agitated depression with insomnia (therapeutic level 50-150 ng/mL) 5

Avoid SSRIs (fluoxetine, paroxetine, sertraline, citalopram) and bupropion as they commonly cause or worsen insomnia. 5, 6

Fourth-Line Medications (Rarely Appropriate)

Other sedating agents only for patients with specific comorbid conditions: 1

• Gabapentin or tiagabine for patients with comorbid seizure disorder or neuropathic pain 1
• Quetiapine or olanzapine only for patients with comorbid psychotic or severe mood disorders 1, 2

The American Academy of Sleep Medicine explicitly warns against atypical antipsychotics for primary insomnia due to weak evidence and significant adverse effects including metabolic syndrome and weight gain. 2

Medications to Avoid

Never prescribe these agents for insomnia: 1

• Traditional benzodiazepines (temazepam, lorazepam, triazolam) due to high dependence potential, cognitive impairment, fall risk, and prolonged half-lives 1, 2
• Barbiturates and chloral hydrate due to dangerous adverse effect profiles 1
• Over-the-counter antihistamines (diphenhydramine, doxylamine) due to lack of efficacy data, anticholinergic burden, and next-day sedation 1, 2
• Herbal supplements (valerian, melatonin supplements) due to insufficient efficacy and safety data for chronic insomnia 1

Note on melatonin: While OTC melatonin supplements are not recommended, prescription ramelteon (a melatonin receptor agonist) has proven efficacy and safety. 1, 2

Special Considerations for Stress-Related Insomnia

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, increasing cortisol, noradrenaline, and corticotropin-releasing hormone, which promote wakefulness and create a vicious cycle with insomnia. 7

For patients with post-traumatic stress or significant anxiety: 8, 9

• Prazosin (alpha-1 antagonist) shows large reductions in nightmares and insomnia in PTSD patients 8, 9
• CBT-I combined with imagery rehearsal therapy for nightmares demonstrates significant improvements 8, 9, 10
• Avoid benzodiazepines as evidence shows they are not useful for PTSD-related sleep disorders 9

Critical Prescribing Guidelines

All pharmacotherapy must include patient education about: 1

• Treatment goals and realistic expectations (medications improve but rarely eliminate insomnia) 1
• Safety concerns including driving impairment, complex sleep behaviors, and fall risk 1, 4
• Potential side effects and drug interactions 1
• Risk of rebound insomnia upon discontinuation 1
• Importance of concurrent behavioral therapy 1

Follow-up requirements: 1

• Assess every few weeks initially for effectiveness and adverse effects 1
• Use the lowest effective maintenance dose 1
• Taper medications when conditions allow (facilitated by CBT-I) 1
• Long-term use (nightly, intermittent 3x/week, or as-needed) may be indicated for severe/refractory insomnia 1

Discontinuation strategy: 1, 4

• Taper over 10-14 days to minimize withdrawal symptoms including anxiety, irritability, rebound insomnia, and electric shock-like sensations 4, 6
• Monitor for withdrawal signs including headache, sweating, nausea, dizziness, and confusion 4, 6

Combination Therapy

Combining CBT-I with pharmacotherapy provides better short-term outcomes than either alone, with behavioral therapy providing longer-term sustained benefit. 1 In older adults, combination therapy was more efficacious than either modality alone, though sleep improvements were better sustained over time with behavioral treatment. 1

Common Pitfalls to Avoid

• Starting with benzodiazepines instead of BzRAs or ramelteon increases risk of dependence, cognitive impairment, and falls, especially in elderly patients 1, 2
• Prescribing without concurrent CBT-I misses the most effective long-term treatment 1, 2
• Using SSRIs for insomnia when they commonly cause or worsen sleep disturbances 5, 6
• Failing to screen for sleep apnea or periodic limb movements which are highly prevalent in stress-related insomnia and require different treatment 9, 10
• Not allowing adequate time for sleep (7-8 hours) when prescribing zolpidem, increasing risk of next-day impairment 4
• Prescribing long-acting benzodiazepines to elderly patients who have reduced clearance and increased sensitivity to peak drug effects 1