Pharmacotherapy for Sleep Disorders

Principles - Sleep Rx Rules

• Goal: Improve sleep quality & quantity, enhance daytime function.
• Always: Identify & treat underlying medical/psychiatric causes first.
• Prioritize: Non-pharmacological therapy (CBT-I, sleep hygiene).
• Pharmacotherapy Rules:
  • Use lowest effective dose for shortest duration.
  • Tailor drug choice to insomnia type (onset vs. maintenance) & patient profile.
  • Regularly review need; plan for discontinuation.

⭐ Benzodiazepines (BZDs) and Z-drugs (e.g., Zolpidem) carry risks of tolerance, dependence, and withdrawal; caution with long-term use.

GABAergics - GABA's Dream Team

• Mechanism: Enhance GABAergic transmission via GABA-A receptor modulation, promoting sedation.
• Benzodiazepines (BZDs):
  • E.g., Lorazepam, Diazepam, Temazepam.
  • Broad effects: Sedative, anxiolytic, muscle relaxant, anticonvulsant.
  • Sleep: ↓ latency, ↑ total time; but often ↓ REM & ↓ Stage N3 sleep.
  • ⚠️ Risks: Tolerance, dependence, withdrawal, rebound insomnia, daytime sedation, anterograde amnesia. Antidote: Flumazenil.
• Non-Benzodiazepines (Z-drugs):
  • E.g., Zolpidem (Std & CR for sleep maintenance), Zaleplon (ultra short-acting for sleep initiation), Eszopiclone (longer-acting for sleep maintenance).
  • More selective for α1-GABA-A subunit (primarily sedative effects).
  • Sleep: ↓ latency; generally less disruption of sleep architecture vs BZDs.
  • AEs: Headache, dizziness, complex sleep-related behaviors (e.g., sleepwalking, sleep-driving).

⭐ Z-drugs (e.g., Zolpidem, Eszopiclone) typically cause less disruption of normal sleep stages (REM, N3) compared to most benzodiazepines.

Melatonin/Orexin Agents - Brain's Sleep Switches

• Melatonin Receptor Agonists (MT1/MT2): Mimic melatonin; regulate circadian rhythm.
  • Ramelteon: 8 mg. Sleep-onset insomnia. No abuse. SE: Dizziness, ↑prolactin.
  • Tasimelteon: 20 mg. Non-24-hr sleep-wake disorder (blind).
• Orexin Receptor Antagonists (DORAs): Block orexin A/B → ↓wake drive.
  • Suvorexant: 10-20 mg. Sleep-onset/maintenance. SE: Somnolence, sleep paralysis.
  • Lemborexant: 5-10 mg. Sleep-onset/maintenance.
  • Daridorexant: 25-50 mg. Newer, shorter T½.

⭐ Orexin antagonists (Suvorexant, Lemborexant) block wake-promoting orexins (hypocretins), a distinct mechanism from GABAergics for treating insomnia.

Other Meds - Off-Label Sleepers

• Trazodone: SARI; priapism risk (rare). Dose: 25-100 mg.
• Mirtazapine: NaSSA; causes weight gain, sedation. Dose: 7.5-15 mg.
• Doxepin (low-dose): TCA; potent H1 antagonist. Approved for insomnia at 3-6 mg.
• Quetiapine (low-dose): Atypical antipsychotic; H1 blockade. Metabolic S/E. Dose: 25-100 mg.
• Gabapentin/Pregabalin: Anticonvulsants; may help RLS, anxiety.

⭐ Low-dose Doxepin (3-6 mg) is FDA-approved specifically for sleep maintenance insomnia due to its high H1 receptor affinity and minimal anticholinergic effects at this dose range compared to higher doses used for depression.

Clinical Choices - Smart Sleep Scripts

• Use lowest dose (e.g., Doxepin 3-6mg), shortest duration. Taper to stop.
• BZDs/Z-drugs (e.g., Zolpidem 5-10mg): Risks: dependence, falls, complex sleep behaviors.
• Elderly: Prefer Ramelteon. Caution with BZDs, anticholinergics.

⭐ > Z-drugs (Zolpidem) target GABA-A α1 subunit: more sedation, less anxiolysis/myorelaxation vs BZDs.

High‑Yield Points - ⚡ Biggest Takeaways

• Benzodiazepines (BZDs) & Z-drugs (Zolpidem) enhance GABA-A; risk of dependence & next-day sedation.
• Ramelteon, a melatonin agonist, is non-habit forming, good for sleep-onset insomnia.
• Suvorexant, an orexin antagonist, targets wakefulness pathways for insomnia.
• Low-dose Trazodone or Doxepin are antidepressant options for chronic insomnia.
• Modafinil treats narcolepsy by promoting wakefulness; Sodium Oxybate for cataplexy.
• Clonazepam is first-line for REM Sleep Behavior Disorder (RBD).