Dual Orexin Receptor Antagonists (DORAs) for Insomnia Treatment
What Are DORAs and How Do They Work?
Dual orexin receptor antagonists (DORAs) represent a newer class of insomnia medications that work by blocking the wake-promoting orexin system, offering effective sleep improvement without the cognitive impairment seen with traditional hypnotics. 1, 2
The currently available DORAs include:
- Suvorexant - recommended for sleep maintenance insomnia 1
- Lemborexant - offers pharmacokinetic advantages over suvorexant with similar mechanism 1
- Daridorexant - effective for both sleep onset and maintenance 1
Position in Treatment Algorithm
First-Line Approach
- Cognitive Behavioral Therapy for Insomnia (CBT-I) must be initiated before or alongside any DORA therapy, as it provides superior long-term outcomes compared to medication alone 1, 3, 4
- CBT-I includes stimulus control therapy, sleep restriction therapy, cognitive restructuring, relaxation training, and sleep hygiene education 1, 4
When to Consider DORAs
- DORAs should be considered as first-line pharmacotherapy alongside traditional benzodiazepine receptor agonists (BzRAs) when CBT-I alone is insufficient 1
- Particularly effective for patients with sleep maintenance insomnia or combined sleep onset and maintenance difficulties 1, 5
- Preferred over traditional hypnotics when cognitive function preservation is a priority 2
Clinical Efficacy Profile
Sleep Improvement
- Medium-dose DORAs increase total sleep time by 1.36 standard deviations compared to placebo (95% CI: 0.87-1.86) 2
- High-dose DORAs show even greater effect with SMD = 2.59 (95% CI: 1.89-3.30) for total sleep time 2
- Suvorexant reduces wake after sleep onset by 16-28 minutes with moderate-quality evidence 1
Cognitive Safety Advantage
- DORAs actually improve cognitive performance on standardized testing (DSST scores), unlike traditional hypnotics which impair cognition 2
- Low-dose DORA: SMD = 0.77 (95% CI: 0.33-1.20) for cognitive improvement 2
- Medium-dose DORA: SMD = 1.58 (95% CI: 1.11-2.05) for cognitive improvement 2
- This contrasts sharply with zolpidem, which shows cognitive impairment (SMD = -0.39 to -0.88 depending on dose) 2
Comparison with Traditional Hypnotics
DORAs vs. Zolpidem
- Zolpidem causes next-morning psychomotor and memory impairment that persists 7.5 to 11.5 hours after dosing, even when patients don't perceive sedation 6
- Zolpidem increases fall risk (OR 4.28, P<0.001) and hip fracture risk (RR 1.92,95% CI 1.65-2.24) 7
- DORAs do not show these cognitive and fall risks 2
DORAs vs. Eszopiclone
- Eszopiclone improves sleep latency by 25 minutes and total sleep time by 29 minutes 6
- However, eszopiclone's safety profile regarding cognition remains unverified, with reports of memory impairment (1-1.3% of patients) and confusion (2.5-3% of patients) 6, 2
- DORAs offer comparable sleep efficacy without these cognitive concerns 2
Specific DORA Medications
Suvorexant
- Recommended specifically for sleep maintenance insomnia 1
- Reduces wake after sleep onset by 16-28 minutes with moderate-quality evidence 1
- Well-established safety profile among the DORA class 1
Lemborexant
- Offers pharmacokinetic advantages over suvorexant with similar mechanism of action 1
- Counsel patients about expected somnolence risk and avoid driving/hazardous activities until response is known 1
- Must ensure CBT-I has been initiated or attempted before prescribing 1
Daridorexant
- Effective for both sleep onset and maintenance 1
- Discontinue any prior ineffective hypnotic (like zolpidem) completely before starting daridorexant 1
- Should be combined with optimized CBT-I for best outcomes 1
Implementation Strategy
Starting DORA Therapy
- Implement or optimize CBT-I first - this is non-negotiable 1, 3
- Assess primary sleep complaint: onset vs. maintenance vs. both 1
- Consider patient-specific factors: age, comorbidities, substance abuse history 1
- For patients with substance abuse history, DORAs are preferred over benzodiazepines 1
Monitoring and Follow-Up
- Reassess after 1-2 weeks to evaluate efficacy on sleep latency, sleep maintenance, and daytime functioning 1
- Monitor for adverse effects including morning sedation and somnolence 1
- Continue CBT-I throughout medication treatment - pharmacotherapy supplements, not replaces, behavioral interventions 1, 3
- Periodic reassessment is essential; avoid continuing long-term without re-evaluation 1
Critical Safety Considerations
Advantages Over Traditional Hypnotics
- No cognitive impairment - unlike zolpidem and benzodiazepines 2
- Lower risk of complex sleep behaviors (sleep-driving, sleep-walking) compared to BzRAs 1, 7
- No evidence of increased fall or fracture risk unlike zolpidem 7
- Lower abuse and dependence potential compared to benzodiazepines 1, 8
Precautions
- Counsel about somnolence risk, particularly with lemborexant 1
- Avoid driving or hazardous activities until individual response is known 1
- If insomnia persists beyond 7-10 days, evaluate for underlying sleep disorders like sleep apnea or restless legs syndrome 1
Common Pitfalls to Avoid
- Never prescribe DORAs without implementing CBT-I - behavioral interventions provide more sustained effects than medication alone 1, 3
- Don't continue ineffective hypnotics alongside DORAs - discontinue prior medications completely before starting 1
- Avoid long-term use without periodic reassessment - regularly evaluate continued need 1
- Don't ignore underlying sleep disorders - persistent insomnia warrants evaluation for sleep apnea, restless legs syndrome, or circadian rhythm disorders 1
Why DORAs Are Recommended as Best Option
Meta-analysis of 8,702 subjects across 29 studies demonstrates that DORAs are the optimal intervention for insomnia because they effectively induce and maintain sleep without impairing cognition, unlike traditional hypnotics. 2 This unique profile makes them particularly valuable for: