Sleep Medication Pharmacology: Benzodiazepines, Z-Drugs, Orexin Antagonists
Benzodiazepines reduce sleep latency by ~10 min and increase TST by 30–40 min but suppress slow-wave sleep 25–30% and REM 15–20%; orexin receptor antagonists (suvorexant, lemborexant) preserve natural sleep architecture and avoid hangover effects.
| Measure | Value | Unit | Notes |
|---|---|---|---|
| Benzodiazepine sleep latency reduction | 10 | minutes | Holbrook et al. 2000 meta-analysis; pooled RCT data |
| Benzodiazepine TST increase | 30–40 | minutes | Same meta-analysis; comparable to Z-drugs on subjective and objective measures |
| Benzodiazepine SWS suppression | 25–30 | % reduction | Winkler et al. 2014; all GABAergic hypnotics reduce slow-wave amplitude and duration |
| Suvorexant sleep onset improvement vs placebo | ~8 | minutes faster | Herring et al. 2016; 10 and 20 mg doses; no REM/SWS suppression |
| Melatonin vs placebo sleep latency reduction | 7 | minutes | Meta-analysis by Ferracioli-Oda et al. 2013; smallest effect of common agents |
Mechanisms of Sleep Medications
GABAergic Agents (Benzodiazepines, Z-Drugs)
GABA-A receptor positive allosteric modulators enhance chloride influx when GABA binds. This hyperpolarizes neurons across sleep-promoting and wake-promoting circuits indiscriminately. Effect on sleep architecture:
- SWS suppressed: GABAergic modulation reduces delta wave amplitude; less restorative deep sleep
- Sleep spindles increased: N2 spindle density increases (GABA-A alpha-1/alpha-2 mediated)
- REM suppressed: Overall neural activity reduction reduces REM proportion
- Subjective sleep improved: Despite architectural changes, subjective quality often improves short-term
Orexin Receptor Antagonists (DORAs)
Suvorexant (2014), lemborexant (2019), daridorexant (2022) block OX1R and OX2R. Unlike GABAergic drugs, they specifically silence the wake-promoting signal. Sleep architecture studies:
- REM unchanged or slightly increased
- N3/SWS unchanged
- Sleep efficiency comparable to Z-drugs
- No significant respiratory depression (safer in COPD, mild-moderate sleep apnea)
Histamine H1 Antagonists (Doxylamine, Diphenhydramine)
OTC sleep aids. First-generation antihistamines cross the blood-brain barrier and block H1 receptors in the tuberomammillary nucleus (wake-promoting histaminergic neurons). Tolerance develops within 3–4 nights. Significant anticholinergic burden: dry mouth, urinary retention, blurred vision, cognitive impairment. Strongly avoided in adults >65 (Beers Criteria; associated with cognitive decline risk).
Comparative Pharmacology
| Drug Class | SWS | REM | Dependence | Hangover |
|---|---|---|---|---|
| Benzodiazepines | ↓↓ | ↓ | High | Moderate |
| Z-drugs | ↓↓ | ↓ | Moderate | Low–moderate |
| DORAs | → | →/↑ | Low | Low |
| H1 antagonists | → | → | Low (tolerance) | Moderate |
| Melatonin | → | → | None | None |
Guidelines Summary
AASM 2017 (Sateia et al.) provides the most current recommendations:
- Suvorexant: Moderate evidence; conditional recommendation for sleep maintenance insomnia
- Eszopiclone, zolpidem: Moderate evidence; conditional recommendation; lowest effective dose
- Temazepam: Conditional; shorter courses
- Low-dose doxepin: Specifically for sleep maintenance (H1 blockade at low doses)
- OTC antihistamines, benzodiazepines (other than temazepam): Insufficient evidence; not recommended
- CBT-I over all pharmacotherapy for chronic insomnia: Strong recommendation
Related Pages
Sources
- Holbrook AM et al. — Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ (2000)
- Winkler A et al. — Effect of benzodiazepines and Z-drugs on EEG sleep architecture: a systematic review. Pharmacopsychiatry (2014)
- Herring WJ et al. — Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry (2016)
- Sateia MJ et al. — Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults. J Clin Sleep Med (2017)
Frequently Asked Questions
What is the difference between Z-drugs and benzodiazepines for sleep?
Both classes act on GABA-A receptors but Z-drugs (zolpidem, zaleplon, eszopiclone) were designed with receptor subunit selectivity (alpha-1 subunit) to produce sedation with reduced anxiolytic, muscle relaxant, and anticonvulsant effects. In practice, Z-drugs and benzodiazepines have similar sleep-promoting efficacy, similar SWS/REM suppression, and similar dependence potential. Z-drugs have shorter half-lives, reducing next-day hangover, but next-day driving impairment is still documented with standard doses. The FDA mandated dose reductions for zolpidem in 2013 specifically due to morning-after driving impairment data.
Are orexin receptor antagonists safer than older sleep medications?
DORAs (suvorexant, lemborexant, daridorexant) have a mechanistically different profile: they block orexin wake-promotion rather than globally suppressing neural activity. This preserves sleep architecture more faithfully (no SWS or REM suppression), avoids the cognitive impairment seen with GABAergic drugs, and has lower dependence signal in trials. The main limitations are cost, modest efficacy advantage over Z-drugs in direct comparisons, and potential next-day sedation at higher doses. AASM 2017 guidelines give conditional recommendations for all classes due to limited head-to-head long-term data.