Usage
- Melatonin is primarily prescribed for the short-term treatment of primary insomnia characterized by poor sleep quality, particularly in patients aged 55 or older. It’s also used for insomnia in children with certain neurodevelopmental disorders following specialist initiation. Off-label uses include jet lag, shift work sleep disorder, and other circadian rhythm sleep-wake disorders. Some studies suggest potential benefits for reducing anxiety before and after surgical procedures. It is being investigated for potential use in other conditions, such as autism spectrum disorder and certain types of headache, but evidence is limited.
- Pharmacological classification: Hormone, Chronobiotic, Hypnotic.
- Mechanism of action: Melatonin acts as a chronobiotic agent by mimicking the actions of endogenous melatonin, a hormone naturally produced by the pineal gland that regulates the sleep-wake cycle. Exogenous melatonin binds to melatonin receptors (MT1 and MT2) in the suprachiasmatic nucleus (SCN) of the hypothalamus, promoting sleep onset and regulating circadian rhythms.
Alternate Names
- N-acetyl-5-methoxytryptamine
- Brand names: Circadin, Adaflex, Ceyesto, Slenyto, Syncrodin, Melotin
How It Works
- Pharmacodynamics: Melatonin binds to MT1 and MT2 receptors in the SCN, promoting sleep onset and regulating circadian rhythms. It has also demonstrated antioxidant, anti-inflammatory, and immunomodulatory effects, although their clinical significance in sleep disorders is not fully understood.
- Pharmacokinetics:
- Absorption: Melatonin is rapidly absorbed after oral administration.
- Metabolism: Primarily metabolized in the liver, mainly by CYP1A2, to 6-sulfatoxymelatonin.
- Elimination: Excreted primarily in the urine. The half-life is relatively short (around 30-50 minutes), but extended-release formulations provide prolonged melatonin release.
- Mode of action: Binds to MT1 and MT2 receptors in the suprachiasmatic nucleus, synchronizing the circadian rhythm with the light-dark cycle.
- Receptor binding: Melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus, and possibly other areas of the brain.
- Elimination pathways: Hepatic metabolism via CYP1A2, followed by renal excretion of metabolites.
Dosage
Standard Dosage
Adults:
- Primary Insomnia: 2 mg of a prolonged-release formulation, taken 1-2 hours before bedtime, after food. This can be increased to a maximum of 5mg after one to two weeks if the initial dose is inadequate. Treatment should not exceed 13 weeks.
- Jet Lag: 0.5 to 5 mg taken close to the target bedtime at the destination, on arrival. Doses should not be taken before 8 PM or after 4 AM at the destination. Max 5 days, Max 16 courses/year.
- Other circadian rhythm disorders: Initial doses of 0.5mg have been used, this may increase if needed.
Children:
- Use is generally not recommended for children under 18 years of age due to limited safety and efficacy data. For children over 2 years, with autism spectrum disorder or Smith-Magenis Syndrome, 1 to 10mg prolonged release has been used, commenced 30-60 minutes before bedtime with food.
Special Cases:
- Elderly Patients: Start with a low dose (1-2 mg immediate-release or 2 mg prolonged-release) given 1 hour before bedtime and increase gradually if needed.
- Patients with Renal Impairment: Caution is advised, as the effect of renal impairment on melatonin pharmacokinetics is not fully understood.
- Patients with Hepatic Dysfunction: Not recommended due to impaired melatonin metabolism and potential for elevated melatonin levels.
- Patients with Comorbid Conditions: Use with caution in patients with autoimmune diseases, epilepsy, depression, or bleeding disorders. Consult specialist advice for individual assessment.
Clinical Use Cases
- Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, and Emergency Situations: The use of melatonin in these settings is largely based on pre-operative use or small clinical trials. Doses of 3-10 mg have been used, often as premedication to reduce anxiety and hemodynamic responses to intubation or aid with sleep/sedation. Optimal doses, timing, and long-term efficacy in these settings remain unclear.
Dosage Adjustments
- Renal/Hepatic dysfunction: Exercise caution in renal impairment, avoid in hepatic dysfunction.
- Metabolic disorders and genetic polymorphisms: Limited data is available for other specific disorders/polymorphisms. Individual assessment is necessary.
Side Effects
Common Side Effects
- Drowsiness
- Headache
- Dizziness
- Nausea
Rare but Serious Side Effects
- Allergic reactions
- Worsening of depression
- Increased seizure frequency
- Bleeding complications (in patients with bleeding disorders)
Long-Term Effects
- Limited data available. Potential concerns about hormonal effects with prolonged use, particularly in children.
Adverse Drug Reactions (ADR)
- Severe allergic reactions (rare).
- Seizures (in susceptible individuals)
Contraindications
- Hypersensitivity to melatonin
- Severe hepatic impairment
- Concurrent use with fluvoxamine or alcohol
Drug Interactions
- CYP1A2 inhibitors: May increase melatonin levels (e.g., fluvoxamine, ciprofloxacin, verapamil, some contraceptives).
- CYP1A2 inducers: May decrease melatonin levels (e.g., carbamazepine, rifampicin).
- CNS depressants: May enhance sedative effects (e.g., benzodiazepines, alcohol).
- Calcium channel blockers: May reduce their hypotensive effect.
- Anticoagulants/Antiplatelets: Theoretical risk of increased bleeding, particularly in patients with existing bleeding disorders.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Limited data available. Considered possibly safe for short-term use. Caution advised during pregnancy.
- Fetal risks: Potential, but limited data on possible effects.
- Breastfeeding: Melatonin is excreted in breast milk. Use with caution during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Mimics endogenous melatonin, binding to MT1 and MT2 receptors, regulating circadian rhythms and promoting sleep.
- Side Effects: Drowsiness, headache, dizziness, nausea, allergic reactions, seizures.
- Contraindications: Hypersensitivity, hepatic impairment, concurrent use with fluvoxamine/alcohol.
- Drug Interactions: CYP1A2 inhibitors/inducers, CNS depressants, calcium channel blockers.
- Pregnancy & Breastfeeding: Caution advised.
- Dosage: Adults: 2 mg prolonged-release, 1-2 hours before bed. Children: not generally recommended. Special cases require adjusted dosing.
- Monitoring Parameters: Sleep quality, daytime sleepiness, adverse effects.
Popular Combinations
- No established or “popular” combinations exist. Melatonin is typically used as monotherapy for sleep disorders. Combination with other sleep aids or sedatives requires careful consideration due to the risk of additive effects.
Precautions
- General Precautions: Assess for underlying medical conditions, allergies, concurrent medications.
- Specific Populations: Caution in pregnant/breastfeeding women, children, elderly, and patients with renal impairment.
- Lifestyle Considerations: Avoid alcohol and operating machinery due to potential drowsiness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Melatonin?
A: The standard adult dosage for insomnia is 2 mg of a prolonged-release formulation taken 1-2 hours before bed. For children aged 2 and above (specifically with ASD or SMS), the dose is 2-10 mg once at night, 30-60 minutes before bed with food. Lower doses (0.5-3mg) are generally recommended for children. Elderly patients should start with lower doses (1-2 mg immediate-release).
Q2: How long does it take for Melatonin to work?
A: Melatonin typically starts working within 30-60 minutes for immediate-release formulations and 1-2 hours for prolonged-release formulations.
Q3: Can I take Melatonin long-term?
A: Generally, melatonin is recommended for short-term use (up to 13 weeks for primary insomnia). Long-term use should be evaluated by a healthcare professional.
Q4: Is Melatonin safe for children?
A: Melatonin use in children should be under the guidance of a specialist. It is not routinely recommended for children under 18 except in specific neurodevelopmental disorders.
Q5: What are the common side effects of Melatonin?
A: Common side effects include drowsiness, headache, dizziness, and nausea.
Q6: Can I take Melatonin if I have liver problems?
A: Melatonin is not recommended for patients with hepatic impairment due to altered metabolism.
Q7: Does Melatonin interact with other medications?
A: Yes, melatonin can interact with several medications, including CYP1A2 inhibitors/inducers, CNS depressants, and calcium channel blockers.
Q8: Can I take Melatonin if I am pregnant or breastfeeding?
A: Melatonin should be used with caution during pregnancy and breastfeeding due to limited safety data. Consult a healthcare professional for advice.
Q9: Can I develop tolerance to Melatonin?
A: Tolerance to melatonin is not typically a concern with short-term use.
Q10: What should I do if I miss a dose of Melatonin?
A: Skip the missed dose and take the next dose at your regular time. Do not double the dose.
