Nonbenzodiazepine Hypnotics

Nonbenzodiazepine hypnotics (zolpidem, zopiclone, eszopiclone, zaleplon), also called Z-drugs, are short-acting sedatives for short-term insomnia. They have little advantage over benzodiazepines in safety, and carry similar dependence risk.

Mechanism. They are selective positive allosteric modulators of GABA-A receptors containing the alpha-1 subunit, causing sedation with less anxiolytic and muscle relaxant effect.

Pharmacokinetics. Zolpidem half-life 2 to 3 hours; zaleplon 1 hour; zopiclone 5 hours; eszopiclone 6 hours. Zolpidem and zopiclone are metabolised by CYP3A4. Food delays onset.

Differences. Zaleplon is the shortest, suited to middle-of-the-night waking. Zopiclone and eszopiclone cause a bitter taste. Zolpidem has the strongest link with complex sleep behaviours and next-day impairment.

• Short-term insomnia: for no more than 2 to 4 weeks, after cognitive behavioural therapy for insomnia and sleep hygiene have been tried or are not available.
• Timing: take immediately before bed, with at least 7 to 8 hours available for sleep.
• Intermittent use: 3 nights each week reduces tolerance.
• Stopping: taper if used for over 2 to 4 weeks, to reduce rebound insomnia.
• Alternatives: melatonin in older adults, low-dose doxepin or trazodone, and orexin receptor antagonists.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: not used. Older adults: lowest dose, and avoid where possible because of falls. Kidney impairment: start at the low dose. Liver impairment: use the low dose, and avoid with hepatic encephalopathy. Regional: availability is uneven; drivers and people in safety-critical jobs must not take doses with less than 8 hours before they wake.

Adverse effects. Next-day drowsiness, dizziness, amnesia, falls, hallucinations, headache, rebound insomnia, and complex sleep behaviours (sleepwalking, sleep driving, sleep eating), which are a boxed concern. Stop the drug at the first episode.

Contraindications. Severe sleep apnoea, severe respiratory insufficiency, severe hepatic impairment, myasthenia gravis, and previous complex sleep behaviour.

Interactions. Alcohol, opioids and other sedatives. Ketoconazole, ritonavir and erythromycin raise zopiclone and eszopiclone levels (reduce the dose). Rifampicin lowers levels.

Monitoring. Duration of use, next-day function, falls, dependence, and complex sleep behaviours.

Referral and escalation. Complex sleep behaviours, dependence, or underlying sleep apnoea or psychiatric illness.