Melatonin

Melatonin is the pineal hormone that signals darkness and sleep timing. It is used for insomnia in adults aged 55 years and over, for insomnia in children with autism spectrum disorder or Smith-Magenis syndrome, and, off-label, for delayed sleep-wake phase disorder and jet lag. It is not habit forming and has few serious adverse effects, but product quality varies and some preparations are unlicensed supplements.

Classification. Hormone, chronobiotic and hypnotic, melatonin receptor agonist.

Mechanism. Agonist at MT1 and MT2 receptors in the suprachiasmatic nucleus, which shifts circadian phase and promotes sleep onset.

Pharmacokinetics. Rapidly absorbed with variable bioavailability (about 15%). Extensive first-pass metabolism by CYP1A2 to 6-hydroxymelatonin. Half-life about 40 to 60 minutes for immediate release and about 3.5 to 4 hours for prolonged release.

All regimens are oral with no loading dose.

Primary insomnia in adults aged 55 years and over (prolonged-release).

• 2 mg once daily, 1 to 2 hours before bedtime, after food.
• Maximum 2 mg daily. Duration: up to 13 weeks; review at 3 weeks.

Insomnia in children and adolescents aged 2 to 18 years with autism spectrum disorder or Smith-Magenis syndrome (prolonged-release, specialist use).

• Start 2 mg once daily, 30 to 60 minutes before bedtime, with or after food.
• Titration: if the response is inadequate after 3 weeks, increase to 5 mg.
• Maximum 10 mg daily. Review at 3 months and stop for a break at least every 6 to 12 months.

Delayed sleep-wake phase disorder and jet lag (off-label, immediate release). 0.5 to 5 mg taken at the desired bedtime, or for jet lag at local bedtime for 2 to 4 days after arrival; lower doses (0.5 to 1 mg) are as effective for many patients.

Dose limits. Liver impairment: avoid in severe disease. Kidney impairment: use cautiously, with no formal adjustment. Fluvoxamine: avoid or reduce to the lowest dose.

Contraindications. Hypersensitivity. Avoid in severe liver impairment, and use cautiously in autoimmune disease and epilepsy.

Serious adverse effects. Uncommon: seizure worsening in epilepsy, mood change, aggression or agitation, hypersensitivity. No known dependence or withdrawal syndrome.

Common adverse effects. Daytime sleepiness, headache, dizziness, vivid dreams, nausea, irritability.

Interactions. Fluvoxamine (a strong CYP1A2 inhibitor) raises levels up to 17-fold and is avoided. Ciprofloxacin and oral oestrogens raise levels. Smoking, rifampicin and carbamazepine lower levels. Alcohol and other sedatives add drowsiness. Caffeine can antagonise the effect. Warfarin effect can change, so check INR.

Common prescribing errors. Taking it too late or with a high-fat meal; using unlicensed products with unknown content; high doses without added benefit; not reviewing the need after 13 weeks.

Special groups.

• Pregnancy: avoid; limited data.
• Breastfeeding: excreted in milk; avoid.
• Children: licensed use is for autism spectrum disorder or Smith-Magenis syndrome only; other use is off-label and specialist.
• Older adults: the licensed group; 2 mg prolonged-release.
• Kidney impairment: use cautiously.
• Liver impairment: avoid in severe disease.
• Regional: availability and regulation vary; in some regions melatonin is sold as an unlicensed supplement and the content may differ from the label.

Formulations. Prolonged-release tablets 2 mg; mini-tablets 1 mg and 5 mg; immediate-release tablets and capsules 0.5 mg to 10 mg; oral liquid in some regions. Swallow prolonged-release tablets whole, after food; do not crush or chew.

Baseline. Sleep history and sleep hygiene, circadian pattern, medicines list for CYP1A2 inhibitors, epilepsy and autoimmune disease, pregnancy status.

Monitoring. Review at 3 weeks. For children, review at 3 months and take a treatment break at least every 6 to 12 months. Ask about daytime sleepiness and mood.

Stopping. No taper is needed; stop after the planned course.

Referral and escalation. Refer to sleep medicine or paediatrics for insomnia that persists after 13 weeks or suspected sleep disorders other than insomnia.