Anxiolytics & Hypnotics: Benzodiazepines, Z-Drugs & Alternatives
Fast relief, real risks, and when the alternatives are smarter
How benzodiazepines and Z-drugs work
GABA-A modulation. Benzodiazepines bind at the α–γ subunit interface of the GABA-A receptor and increase the frequency of chloride channel opening when GABA is present. Barbiturates instead prolong opening and, at high doses, open the channel without GABA, which is why they are far deadlier in overdose. The clinical effects are anxiolysis, sedation, anticonvulsant and muscle-relaxant actions, and anterograde amnesia.
Z-drugs. Zolpidem, zaleplon, and eszopiclone are structurally distinct but act at the benzodiazepine site, preferring α1-containing receptors; they are mainly hypnotic, with little anxiolytic or anticonvulsant effect. Flumazenil reverses both classes.
| Group | Examples | Features | Typical uses |
|---|---|---|---|
| Short-acting | Triazolam, midazolam, alprazolam | Rapid onset; interdose rebound; more misuse; early, intense withdrawal (1–2 days) | Procedural sedation (midazolam), sleep onset |
| Glucuronidated only | Lorazepam, oxazepam, temazepam | No CYP oxidation, no active metabolites | Cirrhosis, older adults, status epilepticus (lorazepam) |
| Long-acting | Diazepam, chlordiazepoxide, clonazepam, flurazepam | Self-tapering; diazepam, chlordiazepoxide, and flurazepam form active metabolites (e.g., nordiazepam) that accumulate | Alcohol withdrawal, tapering, panic bridge (clonazepam) |
When a benzodiazepine is appropriate
- Panic disorder or acute anxiety: a short bridge while an SSRI takes effect, then a taper. A scheduled longer-acting agent such as clonazepam causes less interdose rebound than alprazolam.
- Alcohol withdrawal: first-line, usually symptom-triggered; long-acting agents are favored unless cirrhosis or old age calls for lorazepam or oxazepam.
- Status epilepticus: IV lorazepam first (IM midazolam or IV diazepam are alternatives).
- Catatonia: lorazepam is diagnostic and therapeutic.
- Acute agitation: IM lorazepam, often with an antipsychotic; avoid combining parenteral benzodiazepines with IM olanzapine.
- Procedural sedation: midazolam, valued for its amnesia.
Not maintenance therapy. Benzodiazepines are not long-term treatment for anxiety disorders; SSRIs, SNRIs, and psychotherapy are.
Risks, withdrawal, and tapering
Respiratory depression. A benzodiazepine overdose alone causes sedation but rarely death. Combined with opioids, alcohol, or other depressants, it causes respiratory depression, coma, and death, the subject of a boxed warning; a second boxed warning covers misuse, addiction, physical dependence, and withdrawal. Avoid co-prescribing with opioids whenever possible.
Older adults. Benzodiazepines and Z-drugs increase falls, hip fractures, motor vehicle crashes, cognitive impairment, and delirium, and the Beers Criteria advise avoiding them for insomnia, agitation, or delirium. Paradoxical agitation and disinhibition are more frequent in children and the elderly.
Tolerance and memory. Tolerance to the hypnotic effect develops within weeks, and daily use beyond a few weeks causes physical dependence. Anterograde amnesia, psychomotor slowing, and impaired driving are dose-related and additive with alcohol.
Abrupt discontinuation after regular use causes rebound anxiety and insomnia, tremor, tachycardia, sweating, perceptual disturbances, delirium, and seizures, which can be fatal, as in alcohol withdrawal. Short-acting agents produce earlier and more intense withdrawal.
Tapering. Reduce gradually over weeks to months, often after switching to a long-acting agent such as diazepam or clonazepam, with CBT support.
Hepatic impairment. Lorazepam, oxazepam, and temazepam undergo only glucuronidation and have no active metabolites, so they are preferred in cirrhosis and older adults (the "LOT" trio). Diazepam and chlordiazepoxide require CYP oxidation and accumulate.
Flumazenil. This competitive GABA-A antagonist reverses benzodiazepines and Z-drugs but can precipitate withdrawal seizures in dependent patients or after tricyclic co-ingestion. Reserve it for iatrogenic oversedation in benzodiazepine-naive patients; most overdoses need only airway support.
Non-benzodiazepine options for anxiety
Buspirone. A 5-HT1A partial agonist, buspirone treats GAD alone or as SSRI augmentation, with no sedation, dependence, withdrawal, respiratory depression, or alcohol potentiation, which makes it attractive with a substance use history. It must be taken regularly (2–3 times daily) and needs 2–4 weeks to work, so it is useless as needed and ineffective for panic disorder. Dizziness, headache, and nausea are the usual side effects.
Buspirone has no cross-tolerance with benzodiazepines, so switching from a benzodiazepine still requires a taper.
Hydroxyzine. This sedating first-generation H1 antihistamine relieves anxiety within about an hour without dependence, making it the usual as-needed option. It is anticholinergic (avoid in older adults) and can prolong the QT interval.
Propranolol. For performance-only anxiety, a dose before the event blunts tremor, palpitations, and tachycardia.
Medications for insomnia
CBT-I first. Chronic insomnia (at least 3 nights a week for at least 3 months) calls for a search for contributors such as sleep apnea, depression, medications, caffeine, and alcohol. Cognitive behavioral therapy for insomnia (stimulus control, sleep restriction, cognitive restructuring, and sleep hygiene education) is first line and more durable than drugs. Medication, if added, is short term and matched to the problem: sleep onset or sleep maintenance.
| Drug | Mechanism | Best for | Key cautions |
|---|---|---|---|
| Zolpidem, zaleplon, eszopiclone | GABA-A (α1-preferring) | Onset (zaleplon, zolpidem); onset and maintenance (eszopiclone, extended-release zolpidem) | Complex sleep behaviors (boxed); next-morning impairment; zolpidem 5 mg for women |
| Ramelteon | MT1/MT2 melatonin agonist | Sleep onset | Not controlled, no abuse potential; contraindicated with fluvoxamine |
| Suvorexant, lemborexant, daridorexant | Orexin receptor antagonists | Onset and maintenance | Contraindicated in narcolepsy; sleep paralysis, hypnagogic hallucinations |
| Doxepin 3–6 mg | Selective H1 blockade at low dose | Sleep maintenance | Acceptable in older adults at this dose |
| Trazodone (off-label) | 5-HT2A, H1, and α1 blockade | Not FDA-approved for insomnia | Orthostasis, priapism |
| Diphenhydramine, doxylamine | H1 plus muscarinic blockade | Not recommended | Avoid in older adults: confusion, urinary retention, constipation; rapid tolerance |
Z-drug cautions. Zolpidem, zaleplon, and eszopiclone carry a boxed warning for complex sleep behaviors (sleepwalking, sleep-driving, sleep-eating); if one occurs, stop the drug permanently. Because women clear zolpidem more slowly, the recommended dose for women is 5 mg, and it should be taken only with 7–8 hours left for sleep. Zaleplon's very short half-life suits sleep-onset problems; eszopiclone leaves a bitter, metallic taste.
Non-GABA agents. Ramelteon's lack of abuse potential makes it useful with a substance use history; fluvoxamine, a strong CYP1A2 inhibitor, multiplies its levels. Orexin antagonists reproduce features of orexin deficiency, hence the narcolepsy contraindication. Melatonin itself is mainly useful for circadian rhythm problems such as jet lag and delayed sleep phase.