Is there a use for lower dose orexin (hypocretin) inhibitors, such as suvorexant (Belsomra), in the treatment of insomnia?

Lower Dose Orexin Inhibitors for Insomnia Treatment

Lower dose orexin inhibitors like suvorexant (Belsomra) at 5-10 mg are recommended as a second-line treatment option for insomnia when cognitive behavioral therapy is unsuccessful, offering improved safety profiles while maintaining efficacy for sleep maintenance. 1, 2

Efficacy of Lower Dose Orexin Inhibitors

• Suvorexant has demonstrated efficacy in improving sleep outcomes, with the American Academy of Sleep Medicine suggesting its use for sleep maintenance insomnia in adults at doses of 10,15/20, and 20 mg 3
• At approved lower doses (≤20 mg), suvorexant improves objective sleep measures by:
  • Shortening time to achieve persistent sleep
  • Reducing wake after sleep onset by 16-28 minutes
  • Increasing total sleep time by approximately 10-49.9 minutes 3, 4
• The FDA recommends using the lowest effective dose for patients, with a recommended starting dose of 10 mg, not exceeding 20 mg once daily 2
• If the 10 mg dose is well-tolerated but not effective, the dose can be increased, but should not exceed 20 mg once daily 2

Safety Profile of Lower Dose Orexin Inhibitors

• At approved lower doses (≤20 mg), next-day sedation and driving impairment are much less apparent compared to higher doses 5
• The most common adverse effect is somnolence, occurring in approximately 7% of patients (vs 3% for placebo) 3, 2
• Lower doses minimize the risk of:
  • Sleep paralysis
  • Hypnagogic/hypnopompic hallucinations
  • Cataplexy-like symptoms
  • Complex sleep behaviors 2
• FDA labeling warns that even at lower doses, potential cognitive and behavioral changes may occur, including amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms 3, 2

Clinical Decision Algorithm for Using Lower Dose Orexin Inhibitors

1. First-line treatment: Always begin with cognitive behavioral therapy for insomnia (CBT-I) 1
2. Consider pharmacotherapy only when CBT-I alone is unsuccessful 1
3. When selecting suvorexant:
   • Start with 10 mg taken within 30 minutes of going to bed, with at least 7 hours remaining before planned awakening 2
   • If 10 mg is well-tolerated but ineffective, increase to 20 mg 2
   • For patients taking moderate CYP3A inhibitors, start with 5 mg (not exceeding 10 mg) 2
   • Use lower doses (5-10 mg) in women and obese patients, as drug levels are higher in these populations 5

Special Considerations and Precautions

• Avoid use with strong CYP3A inhibitors 2, 5
• Do not administer with food as it delays drug absorption 5
• No dose adjustment needed for:
  • Advanced age
  • Renal impairment
  • Mild-to-moderate hepatic impairment 5
• Contraindicated in narcolepsy 2
• Monitor for:
  • Worsening depression or suicidal ideation (dose-dependent risk) 2
  • Complex sleep behaviors (sleep-walking, sleep-driving) 2
  • CNS depressant effects that may persist for several days after discontinuation 2

Advantages of Lower Dose Orexin Inhibitors Over Other Hypnotics

• Novel mechanism of action targeting the orexin system specifically involved in sleep-wake regulation 6
• Potentially lower risk of dependence and tolerance compared to benzodiazepines and non-benzodiazepine hypnotics 7
• No evidence of rebound insomnia upon discontinuation 6
• Less cognitive dysfunction and next-day drowsiness at lower doses compared to some traditional hypnotics 6
• Effective for both sleep onset and sleep maintenance insomnia 4

Lower dose orexin inhibitors represent a valuable second-line option for insomnia treatment when used appropriately, with careful attention to dosing and patient-specific factors to minimize adverse effects while maintaining efficacy.