Role in therapy of melatonin for the treatment of insomnia in children and adults

BACKGROUND

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indolamine produced by the pineal gland which may have a role in the biological regulation of circadian rhythms, sleep, and mood. The production and release of melatonin is closely synchronized with the hours of human sleep. Desynchronization in endogenous melatonin secretion can occur in night-shift workers, airplane passengers, and patients with delayed sleep phase syndrome.¹

Melatonin activates G protein-coupled melatonin receptors, which results in the inhibition of adenylatecyclase in target cells.¹² The Mel1a receptor is the presumed site of circadian actions of melatonin, expressed in the hypophysial pars tuberalis and suprachiasmatic nucleus of the hypothalamus.¹ Melatonin may have intracellular sites of action, directly affecting calcium signaling through interactions with adenylate cyclase, phosphodiesterase, and structural proteins.³ Melatonin receptors can be found in various tissues throughout the body, though neural receptors in the suprachiasmatic nucleus are more likely to regulate circadian rhythms.³⁴

Other potential mechanisms of action for melatonin include: the reduction of core body temperature, a measurement linked to the human body subjective sleepiness cycle and inversely related to serum melatonin concentration, and the modification of brain monoamine neurotransmitters, which could initiate events leading to sleep mechanisms.¹

Secretion of melatonin follows a diurnal rhythm of low daytime concentrations (10–20 pg/mL), followed by increased synthesis and secretion in the evening, reaching peak concentrations (80–150 pg/mL) from midnight to 3 am.⁵ The oral bioavailability of melatonin can vary greatly. Low doses of 1 to 5 mg sold over-the-counter at food and drug stores would be expected to result in serum melatonin concentrations 10 to 100 times physiologic concentrations after one hour. Concentrations decline to baseline within roughly four to eight hours post-ingestion.⁶ The serum half-life of orally administered melatonin is 30–60 minutes.⁷⁸ Melatonin is metabolized by hydroxylation in the liver to 6-hydroxymelatonin, which is conjugated with sulfuric or glucuronic acid, and excreted in the urine.¹

We conducted a semi-systematic review of the literature to describe the safety and efficacy of melatonin for the treatment of insomnia. A MEDLINE search for published clinical trials was conducted for the period of January 1966 to July 2013. Search terms included melatonin and insomnia. Searches were limited to include published English-language articles and studies in humans. The literature search yielded 120 publications for potential inclusion. Case reports, pharmacokinetic studies, trials that enrolled only special patient populations (i.e., ADHD, schizophrenia, cognitive impairment, etc.) with insomnia were not included in this review, nor were studies which primarily evaluated extended-release melatonin. Elimination of these trials yielded a total of 10 clinical trials evaluating the use of melatonin for insomnia in children and adults, which are summarized in Tables 1 and 2, respectively.

Table 1. Efficacy and safety of melatonin in children

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Table 2. Efficacy and safety of melatonin in adults

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SAFETY

Reporting of adverse drug reactions in children varied in clinical trials. The most common adverse events were transient and included the following: red eyes and earlobes, yawning, cold feeling, headache, dizziness, and abdominal pain.^9–12 In one trial, seven of 27 children receiving melatonin reported feeling cold, having decrease in appetite, dizziness, and decreased mood after first intake of medication. In the placebo group, three of 35 children were reported to have headache, nausea, dizziness, and increased appetite. No adverse events were reported after three days of therapy initiation.¹⁰ Mild transient headaches during the first two days of melatonin therapy were reported in two of 11 children receiving melatonin in another trial.¹¹ One child receiving melatonin developed mild generalized epilepsy four months after the initiation of therapy and was continued on melatonin. No adverse events were reported for children receiving placebo.¹¹

Adverse events were rarely assessed during clinical trials for adult patients.^13–18 Melatonin was attributed to adverse events in a total of four patients in one trial, which included: slight headache, odd taste in mouth, and feeling of “muzziness”.¹³ Aging patients who received melatonin 3 mg nightly experienced largely elevated melatonin levels as well as hypothermia; an effect which was not seen at lower doses. Temperatures decreased roughly 0.2°C two to three hours after bedtime compared to melatonin 0.1 and 0.3 mg doses.¹⁷ In a toxicology assessment of 10 mg melatonin for a 28 day period, adverse events were mild and similar to placebo, which included: somnolence, headache, fatigue, and cognitive alteration.¹⁹ No median lethal dose has been determined.²⁰

DRUG INTERACTIONS

There have been multiple case reports associating melatonin with minor bleeding and a decrease in prothrombin activity in persons taking anticoagulants such as warfarin.²¹ It is believed that there is a moderate increase in bleeds when concomitantly using antiplatelet and non-steroidal anti-inflammatory drugs as well.²¹ Melatonin may have an effect on glucose utilization and increasing insulin resistance. Theoretically, melatonin could decrease efficacy in hypoglycemic drugs such as insulin, glyburide, glipizide, and tolbutamide.²² Caffeine consumption can decrease endogenous melatonin levels, and theoretically would decrease effectiveness of melatonin.²³ The use of contraceptive medications, fluvoxamine, and verapamil could increase the adverse effects of melatonin.^24–26 Melatonin can decrease the effectiveness of nifedipine; coadministration of melatonin 5 mg at bedtime and nifedipine 30–60 mg daily has been shown to increase systolic blood pressure an average of 6.5 mmHg and diastolic an average of 4.9 mmHg. Heart rate increased by 3.9 bpm.²⁷

PLACE IN THERAPY

The American Academy of Pediatrics consensus statement on the pharmacologic management of insomnia in children and adolescents does not provide guidelines for these populations due to lack of large-scale safety and efficacy clinical trials.²⁸ The American Academy of Child and Adolescent Psychiatry states that in most cases, non-pharmacological, behavioral therapy is first-line treatment in children with insomnia. The guideline states that current safety and efficacy data regarding medication use in the pediatric population is limited to the extent that no recommendations could be made between different sleep agents in this population. It was stated that the pediatric safety and efficacy literature is fairly robust for the use of melatonin, and melatonin may be helpful in reducing sleep-onset latency when taken at bedtime.²⁹

Clinical guidelines for the evaluation and management of chronic insomnia in adults recommend the use of short/intermediate acting benzodiazepine receptor agonists (triazolam, zolpidem, eszopiclone, zaleplon, and temazepam) or ramelteon for the treatment of primary insomnia. The use of sedating antidepressants (trazodone, amitriptyline, doxepin, and mirtazapine), sedating anticonvulsants (gabapentin and tiagabine), or antipsychotic medication (quetiapine and olanzapine) may be suitable in some patients, especially when insomnia is secondary to a comorbid disease state which can be treated with these medications. It is recommended to avoid off-label use of antipsychotic medications and antiepileptic medications as evidence is insufficient. It is recommended to avoid the use of FDA approved medications for insomnia including: chloral hydrate, barbiturates, and meprobamate due to adverse effects, tolerance, and low therapeutic index. It is stated that insufficient safety and efficacy data are available for the use of over-the-counter antihistamine products. Melatonin was stated to have shown a small effect on sleep latency and no effect on waking after sleep onset or total sleep time. These guidelines do not recommend melatonin for the chronic treatment of insomnia based on lack of long-term studies.³⁰

The American Geriatrics Society recommendations for management of sleep disorders in older persons state that cognitive behavioral therapy is an effective treatment for insomnia (IA). It was stated that the use of non-benzodiazepines and the melatonin receptor agonists are the safest and most efficacious hypnotic drugs currently available (II-IIIB evidence), though melatonin was not specifically mentioned. The use of antihistamines, antidepressants, anticonvulsants, and antipsychotics was cited to be associated with more risks than benefits in the treatment of insomnia (II-IIIB evidence) in geriatric patients.³¹

Based on the available literature, melatonin is associated with modest benefit in both subjective and objective sleep measurements when administered to children and adults in the evening before bedtime. Melatonin is a safe, non-addictive alternative to other sedative/hypnotic medications used in insomnia. The risks for drug-drug interactions and adverse events are low. Melatonin should be considered a reasonable therapeutic option for the management of insomnia in pediatric populations after behavioral therapy has been initiated. This recommendation is based on lack of consensus guidelines for the management of insomnia in children, a minimal side effect profile found in clinical trials, and modest efficacy in clinical trials. Melatonin should be considered a second-line treatment for insomnia in adults, after benzodiazepines and benzodiazepine receptor agonists in patients who are not at risk for abusing controlled medications; or in patients who have a comorbid illness which could receive dual benefit if treated with sedating psychotropic medication such an antidepressant, anticonvulsant, or antipsychotic at bedtime. Melatonin may be particularly useful in adult patients with addictive or abusive behaviors towards controlled substances or alcohol and who would not receive additional benefit from a sedating psychotropic or anticonvulsant medication at bedtime for a non-sleep related indication.