Zolpidem

Zolpidem is a short-acting non-benzodiazepine hypnotic (Z-drug) used for short-term insomnia. It acts quickly and has a short half-life, which limits next-day sedation but does not remove the risks of complex sleep behaviours, dependence or impaired driving. Doses differ by sex and age.

Classification. Non-benzodiazepine hypnotic, imidazopyridine.

Mechanism. Selective positive modulation of GABA-A receptors containing the alpha-1 subunit, which gives sedation with little anxiolytic or muscle relaxant effect.

Pharmacokinetics. Rapid absorption, peak in 30 to 120 minutes; food delays and reduces absorption. Metabolised by CYP3A4 to inactive metabolites. Half-life about 2.5 hours (longer in older adults and liver impairment).

All regimens are oral with no loading dose.

Insomnia, adults (short term).

• 10 mg immediately before bed (5 mg for women and in some labels for all adults).
• Maximum 10 mg daily. Use the lowest effective dose.
• Duration: no longer than 2 to 4 weeks, including the taper.

Older adults and liver impairment. 5 mg at bedtime; maximum 5 mg.

Sublingual form for middle-of-night waking (licensed in some regions). 1.75 mg for women and 3.5 mg for men, taken only if at least 4 hours of sleep time remain.

Dose limits. Strong CYP3A4 inhibitors (ketoconazole, ritonavir) and CNS depressants: reduce to 5 mg. Kidney impairment: no adjustment.

Contraindications. Severe sleep apnoea, myasthenia gravis, severe respiratory insufficiency, severe liver impairment, previous complex sleep behaviour with a hypnotic, hypersensitivity. Major warning of complex sleep behaviours (sleep-walking, sleep-driving, eating and other activities while not fully awake), sometimes fatal.

Serious adverse effects. Complex sleep behaviours, next-day impairment of driving and alertness, anterograde amnesia, hallucinations, depression and suicidality, respiratory depression (with other sedatives), dependence and withdrawal, falls and fractures.

Common adverse effects. Drowsiness, dizziness, headache, nausea, diarrhoea, memory impairment.

Interactions. Alcohol, opioids and other sedatives add respiratory depression and sedation. Rifampicin lowers levels sharply; ketoconazole, ritonavir and erythromycin raise them. Sertraline can raise levels modestly.

Common prescribing errors. Taking after a meal; dosing in the middle of the night without enough time to sleep; prescribing 10 mg to women or older adults; combining with alcohol; long-term use.

Special groups.

• Pregnancy: avoid; neonatal sedation and withdrawal with late exposure.
• Breastfeeding: small amounts in milk; avoid or use with infant monitoring.
• Children: not advised.
• Older adults: 5 mg; high risk of falls and confusion.
• Kidney impairment: no adjustment.
• Liver impairment: 5 mg; avoid in severe disease.

Formulations. Tablets 5 mg and 10 mg; extended-release tablets 6.25 mg and 12.5 mg; sublingual tablets 1.75 mg, 3.5 mg, 5 mg and 10 mg in some regions. Swallow immediately before getting into bed, on an empty stomach, with at least 7 to 8 hours of sleep time available.

Baseline. Sleep history and sleep hygiene, alcohol and sedative use, respiratory status, depression and suicide risk, driving requirements, medicines list.

Monitoring. Review at 1 to 2 weeks and at the end of the planned course. Ask about complex sleep behaviours, next-day impairment and escalating use.

Stopping. After more than 2 weeks of nightly use, reduce the dose by 5 to 10% every 1 to 2 weeks or reduce frequency; abrupt stopping can cause rebound insomnia.

Referral and escalation. Stop the drug at once for complex sleep behaviours. Refer to addiction or psychiatric services for dependence.