#328 RXs for Orexins? The efficacy and safety of orexin antagonists for insomnia
CLINICAL QUESTION
Are orexin antagonists safe and effective for primary insomnia?
BOTTOM LINE
Orexin antagonists help people fall asleep ~9 minutes faster and increase total sleep time by ~19 minutes versus placebo over 1-3 months. About 8% of people taking orexin antagonists will experience next-day somnolence compared to 2% placebo.
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EVIDENCE
- 7 systematic reviews of randomized, controlled trials (RCTs).1-7 Focusing on the most recent and comprehensive. Results statistically significant unless indicated.
- Systematic review1 (13 RCTs, 7875 patients, mean age ~55 years) over ~1-3 months:
- Sleep diary outcomes; compared to placebo, orexin antagonists changed:
- Sleep onset: ~9 minutes faster [example: Baseline 65 minutes, 47 minutes with orexins versus 56 minutes (placebo)].
- Total sleep time: Increased ~19 minutes.
- Time awake after falling asleep: ~9 minutes less.
- Sleep quality: Improved ~5% (example improved 0.2 points on a 4-point scale, not likely clinically meaningful).8
- No clinical difference: Awakenings or feeling refreshed on awakening.
- Other reviews2-6 found similar.
- Response on insomnia score:6 55% versus 42% (placebo), NNT=8.
- One RCT with 12 months follow-up found similar.9
- Adverse events:
- Stopping due to adverse effects: No difference.2,3,7
- Most common adverse events:1
- Somnolence 8.3% versus 2.2% (placebo), number needed to harm (NNH)=16.
- Fatigue, dry mouth, abnormal dreams each ~2-3% versus 1% placebo.
- Effects on falls unclear (4 small observational studies in hospitals): Range from associated with increased fall risk to decreased.10-13
- One observational study suggests fracture risk similar between suvorexant and z-drugs.14
- Sleep diary outcomes; compared to placebo, orexin antagonists changed:
- RCT comparing 5 and 10mg Lemborexant to Zolpidem ER:15
- Sleep onset: Lemborexant ~6 minutes better.
- Time awake after falling asleep: Range from no difference to zolpidem ~15 minutes better.
- Proportion of time asleep: No difference
- Dropout due to adverse events: 0.9% versus 2.7% zolpidem.
- Limitations
- RCTs industry sponsored, use of run-ins, incomplete outcome reporting.
- Similar efficacy16 in those >65.
- Limited evidence suggests minimal withdrawal symptoms.2,13,15,17
- Abuse potential not formally assessed in insomnia RCTs.
- Orexin inhibitors have been associated with sleep paralysis/complex sleep behaviors (example “sleep-driving”).18
- Non-pharmacologic sleep restriction therapy is effective.19
- Lemborexant (available in Canada) price: $48/30 tablets.20
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