What medications can be prescribed for a patient with sleep disturbances, considering their medical history, including potential substance abuse, respiratory disease, neuromuscular disorders, depression, or anxiety?

Medications for Sleep Disturbances

For most patients with chronic insomnia, start with short/intermediate-acting benzodiazepine receptor agonists (BzRAs) such as zolpidem, zaleplon, eszopiclone, or temazepam at the lowest effective dose, or ramelteon for patients with substance use history—but only after initiating Cognitive Behavioral Therapy for Insomnia (CBT-I) as the foundation of treatment. 1, 2

First-Line Approach: Always Start with Behavioral Intervention

• CBT-I must be initiated immediately as the primary treatment for all patients with chronic insomnia, as it provides sustained effects for up to 2 years without risk of dependence or withdrawal 2
• Implement essential sleep hygiene: regular sleep-wake schedule, morning/afternoon exercise, avoiding heavy meals and alcohol, dark/quiet sleep environment, and limiting naps to 15-20 minutes 1, 2
• Never start pharmacotherapy alone without concurrent behavioral interventions, as this creates medication dependence without addressing perpetuating factors 2

Pharmacological Treatment Algorithm

Primary Pharmacological Options (First-Line)

For patients WITHOUT substance use disorder:

• Short/intermediate-acting BzRAs are first-line: zaleplon, zolpidem, eszopiclone, triazolam, or temazepam 1
• Zaleplon and ramelteon have very short half-lives, reduce sleep latency but have minimal effect on sleep maintenance, and are unlikely to cause residual sedation 1
• Eszopiclone and temazepam have longer half-lives, improve sleep maintenance better, but carry higher risk of residual sedation (though still limited to a minority of patients) 1
• Zolpidem dosing must follow FDA-mandated lower doses: 5 mg for immediate-release (not 10 mg) and 6.25 mg for extended-release (not 12.5 mg) due to next-morning impairment risk 1
• Administer at the lowest effective dose and shortest possible duration, with counseling on risks including serious injuries from sleep behaviors (sleepwalking, sleep driving) 1

For patients WITH substance use disorder or abuse history:

• Trazodone 50-100 mg at bedtime is the most appropriate choice, with lower abuse potential than hypnotics 2
• Start with 50 mg at bedtime and titrate to 100 mg if insufficient response after 3-5 days 2
• Ramelteon is specifically appropriate for patients preferring non-DEA-scheduled drugs or those with substance use disorders, particularly for sleep initiation difficulty 1, 3
• Ramelteon demonstrated reduced latency to persistent sleep in multiple trials without abuse potential at doses up to 20 times the recommended therapeutic dose 3

Alternative/Adjunctive Options

Low-dose doxepin:

• Improves sleep efficiency with statistically significant differences versus placebo, though adverse events may increase with longer treatment 1
• No black box warning for suicide risk, but risk for suicidal ideation as a hypnotic agent cannot be excluded 1

Mirtazapine:

• May be especially effective in patients with comorbid depression and anorexia 1
• Provides sedating effects that can address both mood and sleep disturbances 4

Lorazepam (short-acting benzodiazepine):

• Reserved for refractory insomnia in select patients 1
• Must be avoided in older patients and those with cognitive impairment due to decreased cognitive performance 1

Critical Medications to AVOID

Benzodiazepines (General Class)

• Strongly advised against for chronic insomnia treatment despite improving sleep parameters, because harms substantially outweigh benefits 1
• Risks include: dependency and diversion, falls and cognitive impairment in elderly, hypoventilation in patients with respiratory conditions (including sleep apnea and obesity hypoventilation), and neuromuscular diseases 1
• Never prescribe as first-line in substance use disorder patients due to high risk of dependence and abuse 2
• Avoid in older patients due to decreased cognitive performance 1

Trazodone (Except in SUD Patients)

• Advised against for general chronic insomnia based on low-quality evidence and adverse effect profile 1
• No differences in sleep efficiency or discontinuation rates versus placebo in systematic review 1
• Only improved subjective sleep quality, with no differences in sleep onset latency, total sleep time, or wake after sleep onset 1
• Studies had very short durations (mean 1.7 weeks) with follow-up of only 1-4 weeks 1

Antihistamines

• Should be avoided due to daytime sedation, delirium risk, and anticholinergic effects 2
• Strong recommendation to avoid in older adults per 2019 Beers Criteria 1
• Tolerance to sedative effects develops after 3-4 days of continuous use, limiting even short-term benefit 1

Antipsychotics (Quetiapine, Olanzapine, Chlorpromazine)

• Advised against for chronic insomnia due to sparse and unclear evidence with small sample sizes and short treatment durations 1
• All antipsychotics cause known harms including increased risk for death in elderly with dementia-related psychosis and increased suicidal tendencies in children, adolescents, and young adults 1
• May be reserved only for refractory insomnia in palliative care settings where agitation disrupts sleep 1

Triazolam

• Associated with rebound anxiety and not considered a first-line hypnotic 1

Special Population Considerations

Patients with Respiratory Disease (Sleep Apnea, Obesity Hypoventilation)

• Screen for obstructive sleep apnea in patients with snoring, gasping, observed apneas, frequent arousals, or unexplained daytime drowsiness 1, 2
• Primary treatment is CPAP or BiPAP, not pharmacotherapy 1
• Benzodiazepines are contraindicated due to hypoventilation risk 1
• Consider polysomnography for patients with head and neck cancers due to high OSA prevalence 1

Patients with Depression or Anxiety

• When insomnia is comorbid with mild-to-moderate depression, consider bedtime dosing of sedating antidepressants: mirtazapine, nefazodone, or tricyclic antidepressants 4
• Mirtazapine particularly effective when depression coexists with anorexia 1
• Address underlying anxiety and depression as contributing factors to sleep disturbance 1

Elderly Patients

• Benzodiazepines must be avoided due to falls, cognitive impairment, and decreased performance 1
• Ramelteon 4-8 mg reduced latency to persistent sleep in patients ≥65 years in crossover trial 3
• Consider temazepam or other intermediate-acting agents at lower doses if BzRAs are necessary 1

Patients with Neuromuscular Disorders

• Benzodiazepines are contraindicated due to risk of respiratory compromise 1
• Prioritize non-benzodiazepine options like ramelteon or low-dose doxepin 1

Substance Use Disorder Patients

• Trazodone 50-100 mg is the preferred pharmacological choice 2
• Ramelteon is appropriate for those preferring non-DEA-scheduled medications 1
• Benzodiazepines and z-drugs should never be prescribed 2
• In cannabis use disorder, sleep disturbance occurs within 3 days of cessation and lasts up to 14 days; trazodone preferred over hypnotics 2

Monitoring and Duration

• Reassess sleep quality weekly during the first month using validated tools like the Insomnia Severity Index 2
• Plan medication tapering after 4-8 weeks if sleep normalizes 2
• Continue CBT-I even after medication discontinuation to maintain gains 2
• Prescriptions should be limited to a few days, occasional/intermittent use, or courses not exceeding 2 weeks when possible 5
• Maximum course duration ideally 4 weeks to prevent tolerance, dependence, and withdrawal effects 5

Critical Pitfalls to Avoid

• Do not prescribe pharmacotherapy without concurrent behavioral interventions 2
• Do not use benzodiazepines in elderly, cognitively impaired, respiratory disease, neuromuscular disorders, or substance use disorder patients 1, 2
• Do not exceed FDA-mandated lower doses of zolpidem (5 mg immediate-release, 6.25 mg extended-release) 1
• Do not overlook screening for obstructive sleep apnea, which requires CPAP rather than hypnotics 1, 2
• Do not use antihistamines or antipsychotics as routine insomnia treatments 1, 2
• Do not continue medications long-term without reassessment and tapering plans 2, 5