Lemborexant is Superior to Diazepam for Chronic Insomnia
For a patient with chronic insomnia and no history of substance abuse or significant respiratory disease, lemborexant is the better choice over diazepam (note: diazepam is a benzodiazepine, not alprazolam as mentioned in the expanded question). Lemborexant offers superior efficacy for both sleep onset and maintenance with a significantly safer profile, particularly regarding dependence risk, cognitive impairment, and long-term tolerability 1, 2.
Why Lemborexant is Preferred
Evidence-Based Efficacy
Lemborexant demonstrates robust efficacy across multiple sleep parameters, reducing sleep onset latency by 9-13 minutes, wake after sleep onset by 19-22 minutes, and improving sleep efficiency by 6-7% compared to placebo 3, 2.
Long-term effectiveness is proven, with lemborexant maintaining efficacy over extended treatment periods without tolerance development—a critical advantage over benzodiazepines 2, 4.
Network meta-analysis confirms lemborexant's superiority, showing it ranks among the most effective agents for both acute and long-term insomnia treatment, with particular strength in sleep maintenance 2.
Safety Profile Advantages
Minimal dependence and abuse potential distinguishes lemborexant from diazepam, which carries significant risk of physical dependence, withdrawal symptoms, and tolerance requiring dose escalation 1, 4.
Cognitive and psychomotor effects are substantially lower with lemborexant compared to benzodiazepines, which cause marked daytime sedation, cognitive impairment, and increased fall risk—especially problematic in older adults 4, 5.
Complex sleep behaviors (sleep-driving, sleep-walking) are less common with lemborexant than with benzodiazepines and Z-drugs 4, 5.
Somnolence is the primary adverse effect with lemborexant (occurring in approximately 7% vs 3% placebo), which is manageable and dose-dependent, whereas diazepam causes multiple problematic effects including respiratory depression, amnesia, and paradoxical agitation 3, 1.
Why Diazepam Should Be Avoided
Guideline Recommendations Against Benzodiazepines
The American Academy of Sleep Medicine explicitly recommends short/intermediate-acting benzodiazepine receptor agonists (BzRAs) as first-line pharmacotherapy—NOT traditional benzodiazepines like diazepam 5, 1.
Diazepam is a long-acting benzodiazepine with a half-life exceeding 24 hours, leading to drug accumulation, prolonged daytime sedation, and increased risk of falls and cognitive impairment 5, 6.
Major guidelines position traditional benzodiazepines as second or third-line options only, reserved for cases where first-line agents have failed and comorbid anxiety requires treatment 5, 1.
Specific Harms of Diazepam
Observational studies link benzodiazepine use to increased risk of dementia, fractures, and major injury—associations not observed with orexin antagonists like lemborexant 5.
FDA documents warn that benzodiazepines require dose reduction in women and older adults due to cognitive and behavioral changes, including driving impairment 5.
Rapid discontinuation produces withdrawal symptoms including rebound insomnia, similar to barbiturates and alcohol, necessitating careful tapering 5.
Treatment Algorithm
Step 1: Implement Cognitive Behavioral Therapy for Insomnia (CBT-I)
CBT-I must be initiated before or alongside any pharmacotherapy, as it provides superior long-term outcomes with sustained benefits after discontinuation 5, 1.
CBT-I components include stimulus control therapy, sleep restriction therapy, relaxation techniques, and cognitive restructuring, deliverable through individual therapy, group sessions, telephone, web-based modules, or self-help books 1.
Step 2: Add Lemborexant if CBT-I is Insufficient
Start with lemborexant 5 mg at bedtime, as this dose demonstrates optimal balance between efficacy and tolerability, with 10 mg reserved for inadequate response 7, 3.
Lemborexant addresses both sleep onset and maintenance, making it suitable for mixed insomnia presentations without requiring multiple medications 8, 2.
Reassess after 1-2 weeks to evaluate efficacy on sleep latency, maintenance, and daytime functioning, monitoring for somnolence as the primary adverse effect 1.
Step 3: Optimize Dosing Based on Response
If 5 mg lemborexant provides partial benefit, increase to 10 mg rather than adding another agent 7, 3.
If lemborexant is ineffective or not tolerated, consider alternative first-line agents (eszopiclone, zolpidem, ramelteon) or low-dose doxepin 3-6 mg for sleep maintenance 1, 2.
Critical Considerations
When Lemborexant May Not Be Optimal
Patients with hepatic impairment require dose adjustment, though lemborexant remains safer than benzodiazepines which have significantly impaired clearance in liver disease 5, 1.
Cost and insurance coverage may favor older agents, but the superior safety profile justifies lemborexant as preferred therapy when accessible 4.
Common Pitfalls to Avoid
Never use diazepam as first-line insomnia treatment—it lacks specific indication for insomnia and carries unacceptable risk-benefit ratio compared to approved agents 5, 1.
Avoid combining lemborexant with other sedatives, as this significantly increases risks of complex sleep behaviors, cognitive impairment, and falls 1.
Do not continue pharmacotherapy long-term without periodic reassessment and ongoing CBT-I implementation, as behavioral interventions provide more sustained effects 5, 1.
Never abruptly discontinue benzodiazepines if a patient is already taking them—taper gradually while transitioning to lemborexant to prevent withdrawal 5.