What are the safest non‑pharmacologic and pharmacologic sleep aids for adults, including older adults and pregnant or breastfeeding patients?

Safe Sleep Aids for Adults

Cognitive behavioral therapy for insomnia (CBT-I) is the safest and most effective first-line treatment for chronic insomnia in all adult populations, including older adults, and should be initiated before any pharmacologic intervention. 1

Non-Pharmacologic Interventions (First-Line for All Patients)

Cognitive Behavioral Therapy for Insomnia (CBT-I)

• CBT-I provides superior long-term outcomes with effects sustained for up to 2 years without medication-related risks, making it the gold-standard initial treatment. 2
• Core components include sleep restriction/compression therapy (limiting time in bed to match actual sleep time), stimulus control (using bedroom only for sleep/sex, leaving bedroom if unable to sleep within 20 minutes), and cognitive restructuring of maladaptive sleep beliefs. 2
• CBT-I can be delivered via individual therapy, group sessions, telephone programs, or web-based modules, allowing flexible access for most patients. 2
• Sleep hygiene education alone is insufficient for chronic insomnia and must be combined with other CBT-I modalities. 2

Sleep Hygiene Modifications

• Maintain consistent sleep-wake times, avoid caffeine after noon, eliminate evening alcohol, avoid heavy meals within 3 hours of bedtime, and ensure the bedroom is cool, dark, and quiet. 2
• Limit daytime napping to 15-20 minutes before 3 PM, avoid vigorous exercise within 2 hours of bedtime, and limit evening fluid intake to reduce nocturia. 2

Additional Behavioral Strategies

• Exercise improves sleep as effectively as benzodiazepines in some studies and is recommended for all patients with insomnia given its additional health benefits. 3
• Relaxation techniques including progressive muscle relaxation, guided imagery, and diaphragmatic breathing help achieve a calm state conducive to sleep onset. 2

Pharmacologic Interventions (Second-Line After CBT-I Failure)

General Adult Population

For sleep-onset insomnia:

• Ramelteon 8 mg at bedtime is the preferred first-line pharmacologic option due to its minimal adverse effect profile, lack of abuse potential, and effectiveness for reducing sleep latency. 4
• Short-acting Z-drugs (zolpidem 5-10 mg) are an alternative for sleep-onset insomnia but carry risks of falls, cognitive impairment, and potential dependence. 2

For sleep-maintenance insomnia:

• Low-dose doxepin 3-6 mg at bedtime is the preferred agent, acting solely as an H1-receptor antagonist at these doses with adverse events comparable to placebo. 2, 4
• Do not exceed 6 mg doxepin, as higher doses re-engage tricyclic mechanisms and lose the favorable safety margin. 2

For combined sleep-onset and maintenance insomnia:

• Eszopiclone 2-3 mg or extended-release zolpidem 6.25-12.5 mg are options for combined symptoms. 2

For comorbid depression/anxiety with insomnia:

• Mirtazapine 7.5-15 mg at bedtime addresses both mood symptoms and insomnia through H1-histamine antagonism; sedating antidepressants should only be used when comorbid psychiatric conditions exist. 2, 4

Older Adults (≥65 Years)

• Start all medications at the lowest available dose due to reduced drug clearance and increased sensitivity to peak effects in elderly patients. 2
• Ramelteon 8 mg remains the safest first-line option for sleep-onset insomnia in older adults. 4
• Low-dose doxepin 3-6 mg (starting at 3 mg) is the most appropriate medication for sleep-maintenance insomnia in older adults with demonstrated improvement in total sleep time and sleep quality. 2
• Eszopiclone should be started at 1 mg in elderly patients, with titration to 2 mg only if needed. 2
• Zolpidem should be limited to 5 mg in older adults due to increased fall risk. 2

Pregnant and Breastfeeding Patients

• CBT-I is the only recommended treatment for insomnia during pregnancy and breastfeeding, as pharmacologic data are insufficient and potential fetal/neonatal risks outweigh benefits. 1
• Sleep hygiene modifications, relaxation techniques, and addressing pregnancy-related discomforts (nocturia, pain, restless legs) should be prioritized. 2

Medications to Avoid in All Populations

Absolutely Contraindicated or Strongly Discouraged

• Benzodiazepines (temazepam, lorazepam, diazepam, triazolam) should be avoided due to higher risk of falls, cognitive impairment, dependence, respiratory depression, and increased dementia risk, particularly in older adults. 1, 2, 4
• Over-the-counter antihistamines (diphenhydramine, hydroxyzine) should be avoided in elderly patients due to anticholinergic effects that accelerate cognitive decline, cause daytime hypersomnolence, and increase fall risk. 1, 2
• Trazodone is not recommended: it carries hepatotoxicity risk, offers minimal sleep benefit (~10 minutes latency reduction), and has a high adverse-event rate. 1, 2
• Antipsychotics (quetiapine, olanzapine) should never be used for primary insomnia due to black-box warnings for increased mortality, metabolic side-effects, and lack of efficacy data. 1, 2
• Barbiturates and chloral hydrate are not recommended for treatment of insomnia due to safety concerns and lack of evidence. 1, 2

Limited or No Evidence

• Herbal supplements (valerian, melatonin) are not recommended due to lack of efficacy and safety data, poor regulation, and potential for residual sedation. 1, 2
• Melatonin has very low quality evidence for efficacy in elderly insomnia, with meta-analysis showing no clinically significant improvement in sleep quality. 2

Implementation Algorithm

Step 1: Initial Assessment

• Review all medications that may cause or exacerbate insomnia: β-blockers, bronchodilators, corticosteroids, decongestants, diuretics, SSRIs, and SNRIs. 2
• Assess for comorbid conditions including sleep apnea, restless legs syndrome, pain, depression, and anxiety. 2
• Evaluate sleep hygiene practices and identify modifiable environmental factors. 2

Step 2: Initiate CBT-I

• Begin CBT-I immediately as the primary treatment for all patients with chronic insomnia (≥3 months, ≥3 nights/week). 1
• Implement sleep restriction, stimulus control, relaxation techniques, and cognitive restructuring. 2
• Reassess at 2-4 weeks to evaluate response. 2

Step 3: Consider Pharmacotherapy Only After CBT-I Failure

• Use shared decision-making to discuss benefits, harms, and costs of short-term medication use. 1
• Select medication based on symptom pattern: ramelteon or short-acting Z-drugs for sleep-onset; low-dose doxepin for sleep-maintenance; eszopiclone or extended-release zolpidem for combined symptoms. 2
• Start at the lowest dose, especially in older adults. 2
• Follow patients every few weeks initially to assess effectiveness and side effects. 2

Step 4: Long-Term Management

• Employ the lowest effective maintenance dosage and taper when conditions allow. 2
• Medication tapering and discontinuation are facilitated by concurrent CBT-I. 2
• For patients requiring chronic hypnotic medication, administration may be nightly, intermittent (three nights per week), or as needed, with consistent follow-up. 2
• Pharmacologic treatments are intended for short-term use (4-5 weeks); patients should not continue using drugs for extended periods without reassessment. 1

Critical Pitfalls to Avoid

• Do not prescribe hypnotic medication before attempting CBT-I, as behavioral interventions provide superior long-term outcomes and reduce polypharmacy risk. 2
• Never use benzodiazepines as first-line agents in older adults due to unacceptable risk of falls, cognitive impairment, and dependence. 1, 2
• Avoid combining multiple sedating agents (e.g., antihistamines with mirtazapine) as this increases anticholinergic burden and adverse effects. 2
• Do not assume sleep hygiene education alone will suffice for chronic insomnia; it must be combined with other CBT-I modalities. 2
• Medication-induced insomnia is frequently overlooked; β-blockers, diuretics, and SSRIs are common culprits that should be identified and adjusted. 2
• Long-term use of benzodiazepines and Z-drugs is associated with serious adverse effects including dementia, fractures, and serious injury; observational studies demonstrate these risks despite limited reporting in short-term RCTs. 1, 4