Drugs for Insomnia

Drugs for insomnia are used for short-term insomnia and for chronic insomnia when cognitive behavioural therapy for insomnia is not available or has not worked. They do not treat the cause, and insomnia usually has a treatable contributor (pain, depression, anxiety, sleep apnoea, alcohol, caffeine, khat, or medicines).

Mechanism. Benzodiazepines and Z-drugs enhance GABA-A signalling. Melatonin receptor agonists act on circadian timing. Orexin receptor antagonists (suvorexant, lemborexant, daridorexant) block wake-promoting orexin signalling. Low-dose doxepin and sedating antihistamines block histamine H1 receptors. Trazodone and mirtazapine block H1 and 5-HT2 receptors.

Pharmacokinetics. Half-life decides next-day effect: zolpidem 2 to 3 hours, suvorexant 12 hours, lemborexant 17 to 19 hours, daridorexant 8 hours, doxepin 15 hours, diphenhydramine 8 hours (longer in older adults).

Differences. Orexin antagonists carry little dependence or withdrawal, but cost and supply limit use. Sedating antihistamines are widely sold but lose effect quickly and cause anticholinergic effects.

• First: cognitive behavioural therapy for insomnia, sleep hygiene, and treatment of contributors. Medicine is added, not substituted.
• Short-term insomnia: a Z-drug or short-acting benzodiazepine for no more than 1 to 2 weeks, or up to 4 weeks at most.
• Chronic insomnia: an orexin antagonist, low-dose doxepin or prolonged-release melatonin, reviewed every 4 weeks.
• Insomnia with depression or anxiety: treat the condition; use mirtazapine or trazodone at night if sedation helps.
• Older adults and dementia: melatonin or low-dose doxepin; avoid benzodiazepines, Z-drugs and anticholinergics.
• Avoid quetiapine and long-term sedating antihistamines for insomnia alone.
• Intermittent use: 3 nights each week reduces tolerance.
• Stopping: taper after more than 2 to 4 weeks of use; warn about 2 to 3 nights of rebound.

Special groups. Pregnancy: avoid; sleep measures first. Breastfeeding: avoid long-acting agents; melatonin and Z-drugs have limited data. Children: behavioural measures first; melatonin in neurodevelopmental conditions under specialist care. Older adults: lowest dose for the shortest time, with falls assessment. Kidney impairment: usual doses, reduce zolpidem in severe disease.

Liver impairment: halve doses of Z-drugs and avoid orexin antagonists in severe disease. Regional: efavirenz and dolutegravir can cause insomnia and vivid dreams, and khat causes insomnia; stimulant use and shift work are common contributors; sedatives sold without prescription are widely misused.

Adverse effects. Next-day drowsiness, impaired driving, falls, amnesia, complex sleep behaviours, dependence, rebound insomnia, sleep paralysis and vivid dreams (orexin antagonists), anticholinergic effects (antihistamines), and orthostasis (trazodone).

Contraindications. Narcolepsy (orexin antagonists), severe sleep apnoea and respiratory failure (benzodiazepines and Z-drugs), myasthenia gravis, and acute alcohol intoxication.

Interactions. Alcohol and opioids (respiratory depression). Strong CYP3A4 inhibitors (ritonavir, ketoconazole, clarithromycin) raise levels of Z-drugs, orexin antagonists and trazodone, and rifampicin and carbamazepine lower them. Fluvoxamine raises melatonin levels.

Monitoring. Sleep diary, daytime function, duration of treatment, falls, dependence, and mood.

Referral and escalation. Suspected sleep apnoea, restless legs, parasomnias, insomnia beyond 3 months, or insomnia with suicidal thoughts.