Insomnia

Comprehensive Insomnia Pharmacotherapy Table

Drug / Class Mechanism Typical Adult Dose Half-Life (h) Key Indications / Notes Major ADRs Contra / Precautions Monitoring / Considerations
Non-Benzodiazepine Hypnotics (“Z-drugs”)
Zolpidem GABA A , BZ1 receptor modulator 5–10 mg HS; CR 6.25–12.5 mg HS ~2–3 Sleep onset (IR); onset + maintenance (CR) Somnolence, dizziness, amnesia, complex sleep behaviors Hx of SUD; hepatic impairment; elderly (lower dose) Fall risk; next-day impairment; avoid with other CNS depressants
Eszopiclone GABA A modulator 1–3 mg HS ~6–9 (longer in elderly) Onset + maintenance Dysgeusia, headache, somnolence Same as Zolpidem Longer half-life → potential morning sedation
Zaleplon GABA A  modulator 5–10 mg HS ~1 Sleep onset; middle-of-night use if ≥4 h remain Dizziness, somnolence Same as Z-drugs Use if early morning awakenings
Benzodiazepines (BZRAs) Potent GABA A agonists     Less recommended due to dependence      
Temazepam GABA A agonist 15–30 mg HS 3–18 Short-term sleep onset + maintenance Respiratory / CNS depression, tolerance Pregnancy; SUD; elderly Taper if used >2–4 wks
Triazolam Short-acting BZD 0.125–0.25 mg HS 1.5–5 Sleep onset Amnesia, rebound insomnia Same High rebound insomnia risk
Others (Estazolam, Quazepam)* GABA A  Varies Long Less favored clinically Sedation, tolerance Same Not first-line
Orexin Receptor Antagonists (DORAs) Antagonize OX1/OX2 wake-promoting receptors     Useful for onset + maintenance      
Suvorexant Dual orexin antagonist 10–20 mg HS ~12–15 Onset + maintenance Somnolence, headache, abnormal dreams Narcolepsy, severe hepatic CNS depression; avoid with strong CYP3A inhibitors
Lemborexant Dual orexin antagonist 5–10 mg HS ~17–19 Onset + maintenance Drowsiness, abnormal dreams Same as suvorexant Potential next-day impairment
Daridorexant Dual orexin antagonist 25–50 mg HS ~8 Onset + maintenance; daytime functioning benefit at 50 mg Somnolence, headache Same Improve daytime function at higher dose
Melatonin & Melatonin Receptor Agonists MT1/MT2 receptor agonists     Lower risk of dependence; useful for onset      
Melatonin (supplement) Exogenous melatonin 0.1–5 mg HS Short Circadian related insomnia; elderly Headache, somnolence Pregnancy caution OTC; variable quality
Ramelteon MT1/MT2 agonist 8 mg HS ~1–2 (active metabolite ~2–5) Sleep onset trouble; no tolerance / withdrawal Dizziness, somnolence Coadmin with CYP1A2 inhibitors; hepatic Good for hx of SUD
Antidepressants (Sedating) Often antihistamine / serotonergic     Often off-label except doxepin      
Doxepin (low-dose) H1 antagonist at low dose 3–6 mg HS ~15 Sleep maintenance (FDA approved) Somnolence, dry mouth Urinary retention, glaucoma Avoid at higher antidepressant doses
Trazodone† 5-HT2 antagonist / reuptake inhibitor 25–100 mg HS ~9 Off-label; use if depression comorbidity Orthostatic hypotension, sedation MAOI co-use Weak evidence
Mirtazapine† α2/5-HT2/3 antagonist 7.5–15 mg HS Long Off-label, depression comorbidity Weight gain, sedation Caution in elderly Longer half-life
Amitriptyline† TCA (antihistamine) 10–50 mg HS ~30 Off-label Anticholinergic, cardiac Elderly, glaucoma Avoid in frail/elderly
Other/Off-Label
Diphenhydramine H1 antagonist 25–50 mg HS ~4–8 OTC; occasional use Anticholinergic, sedation Elderly, glaucoma Not recommended long-term
Gabapentin† GABA analogue 100–900 mg HS ~5–9 Off-label; restless legs / neuropathic pain Dizziness, somnolence Renal dosing Not first-line
Hydroxyzine H1 antagonist 25–50 mg HS ~20–25 Off-label, pruritus benefit Anticholinergic Elderly Avoid chronic use

Drug Selection Matrix

Clinical Scenario (Decision Node) Preferred (First-Line) Acceptable Alternatives Avoid / Last-Line Clinical Rationale
Sleep ONSET insomnia Ramelteon Melatonin Benzodiazepines Non-habit forming; minimal residual sedation
Zaleplon Zolpidem IR (low dose) Diphenhydramine Short half-life targets onset
Sleep MAINTENANCE insomnia Low-dose Doxepin (3–6 mg) DORA Long-acting BZDs H1 blockade / orexin inhibition preserves sleep
DORA (daridorexant) Zolpidem CR Anticholinergics Lower tolerance/dependence risk
Onset + Maintenance DORA Eszopiclone Benzodiazepines Addresses both phases of sleep
Eszopiclone Zolpidem CR Diphenhydramine Longer half-life but less dependence
Elderly (≥65 yrs) Ramelteon Low-dose Doxepin TCAs, BZDs Beers Criteria compliance
DORA Melatonin Diphenhydramine Reduced falls/cognitive risk
History of SUD Ramelteon Doxepin Z-drugs, BZDs No euphoria or dependence
Melatonin DORA    
High fall risk / delirium risk Ramelteon Doxepin BZDs Minimal psychomotor impairment
DORA Melatonin Anticholinergics  
Comorbid depression Trazodone Mirtazapine Z-drugs alone Dual benefit for mood + sleep
Neuropathic pain / RLS Gabapentin Doxepin BZDs Treats underlying driver
Short-term inpatient insomnia Zaleplon Zolpidem IR Long-acting agents Rapid onset, short duration
Chronic insomnia (>4–6 wks) DORA Doxepin Benzodiazepines Lower tolerance & withdrawal

Agent-Focused Comparison (Pharmacist Quick-Reference)

Drug/Class Best for Dependence Risk Next-Day Sedation Half-Life Key Pharmacist Notes
Ramelteon Onset None Minimal ~1–2 h Ideal for elderly/SUD
Melatonin Circadian None Minimal Short Variable OTC quality
Zaleplon Onset Low–Mod Minimal ~1 h Middle-of-night dosing
Zolpidem IR Onset Moderate Moderate ~2–3 h Complex sleep behaviors
Zolpidem CR Maintenance Moderate ↑ Longer Falls risk
Eszopiclone Both Moderate Moderate ~6–9 h Metallic taste
Doxepin (3–6 mg) Maintenance None Low ~15 h Avoid anticholinergic doses
DORA (daridorexant) Both Low Low–Mod ~8 h Improves daytime function
Trazodone Depression-related Low Moderate ~9 h Orthostasis
Mirtazapine Depression/anxiety Low High Long Weight gain
Benzodiazepines Refractory only High High Variable Tolerance, withdrawal
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