Antihistamines are available over the counter and are marketed to treat symptoms of insomnia in adults. One of the more frequently used antihistamines is diphenhydramine, an H1 receptor antagonist that has effects on both the peripheral and central nervous systems. In the central nervous system, histamine is produced in the posterior hypothalamus. H1 receptor sites are located in the frontal lobe and deep structures of the brain. Histamine is considered a wakefulness promoter as it is involved in arousals, memory, cognition, and regulation of sleep-wake cycles.
Antihistamines are absorbed via the gastrointestinal tract and have a peak blood and tissue level in 2 h. Antihistamines given shortly before bedtime lead to significant decrease in sleep latency time and decrease in the number of awakenings. Centrally acting H1 antagonists have been found to suppress REM sleep. Duration of treatment with an antihistamine is usually 4–6 h. The half-life of diphenhydramine is shorter in children than it is in adults. The lowest effective dose in children is 0.5 mg/kg with a maximum dose of 25 mg. Adverse effects at therapeutic doses include drowsiness. Overdoses can produce anticholinergic effects that include dilated pupils, flushing, hyperthermia, dry mouth/skin, and agitations/hallucinations (blind as a bat, red as a beet, hot as a hare, dry as a bone, mad as a hatter). Rarely, overdoses can produce seizures, catatonic stupor, cardiac rhythm disturbances, and respiratory insufficiency.
Melatonin and Melatonin Agonists
Melatonin is a hormone that is secreted by the pineal gland. The pineal gland secretes this hormone in a circadian pattern with high plasma levels during the night and low levels during the day, but its release is suppressed by light exposure during the night. One to 2 h prior to bedtime, plasma melatonin levels usually increase to 10–15-fold higher than daytime levels. Melatonin is at very low levels during the second and third month of life and then it steadily increases. During this time, babies rely on the mothers circadian melatonin levels through breast milk and therefore the babies follow the circadian pattern of the mother.
Melatonin is frequently used for delayed sleep phase syndrome and jet lag as it may have a phase-shifting effect on the suprachiasmatic nucleus. Normal nocturnal plasma ranges in adults are around 50–500 pcg/ml. In adults, taking melatonin in low doses of 0.1–0.3 mg 2 h prior to bedtime is thought to be effective in raising the plasma melatonin to normal levels. The doses which may be effective in children are unclear [3, 4, 15–19].
Melatonin is used in children with insomnia due to circadian factors such as sleep phase delay disorder and blindness and patients with midline brain defects such as agenesis of corpus collosum as this may affect the pineal gland. Melatonin has also been used in patients with ADHD and chronic insomnia to reduce sleep onset time. Any data on efficacy in any of these conditions?
Ramelteon, a melatonin receptor agonist, has been approved for use in patients 18 years and older with sleep onset insomnia [20, 21]. The half-life of this drug is about 1–3 h. Common side effects include headache, somnolence, and fatigue. It may be considered in adolescents with sleep phase delay syndrome. However, no clinical trials are available for patients younger than 18 years old.
Tasimelteon is a melatonin receptor agonist that was released by the FDA for the treatment of non-24-h sleep-wake disorder in 2014. It has an affinity for human melatonin receptors MT1 and MT2, with a higher affinity for the latter. The clinical trials were done in blind adults with a circadian rhythm sleep disorder [22, 23]. Safety and efficacy have not been established in pediatric patients. There is a hypothetical possibility that this new medication may be useful to help entrain the sleep of children with significant circadian disruption to a more predictable schedule. However, to date, there are no pediatric studies available.
Melatonin can cause enhanced immune function, and therefore it should be used with caution in patients on immunosuppressant medications and/or with immune disorders. The FDA does not regulate the use of melatonin as it is currently used as a dietary supplement. It should be noted that melatonin and melatonin agonists lack the potential for addiction associated with some other hypnotics.
Clonidine is an alpha2 receptor agonist. It is commonly used to treat hypertension, but it has also been found to have sedative effects. The exact mechanism of this drug is unknown, but it has been postulated that clonidine acts on the presynaptic terminals of noradrenergic neurons that leads to decrease in norepinephrine release. The onset on this drug is within 1 h and peak effects are within 2–4 h. It is excreted primarily in urine. Side effects include anticholinergic effects, hypotension, and bradycardia. Clonidine also leads to REM suppression and REM rebound with discontinuation. Clonidine has been widely used in pediatric patients with ADHD and/or neurocognitive impairments and sleep disorders . There is no specified dose approved for hypnotic use, but often, doses of 50 mcg per day is used and gradually increased.
Benzodiazepines are hypnotics that act as a GABA receptor agonist. The most commonly used benzodiazepine for sleep in children is clonazepam. It is also used for arousal parasomnias such as sleep walking and sleep terrors in children . Clonazepam may allow the child to sleep throughout the night and is thought to decrease the arousal threshold and is usually prescribed at a dose of 0.25–0.5 mg. It is available in quick dissolving wafer formulation for children that cannot swallow pills. Benzodiazepines may lead to muscle relaxation, and therefore caution is advised in children with obstructive sleep apnea as it may exacerbate the condition.
Selective Benzodiazepine Receptor Agonist (AKA Non-Benzodiazepine Hypnotics)
Selective benzodiazepine receptor agonist including zolpidem, eszolpiclone, and zaleplon are thought to offer some advantages compared to nonselective benzodiazepines; at low dosages, they are thought to preserve the overall sleep architecture and may have less insomnia rebound effects after discontinuation when compared to nonselective benzodiazepines. These medications only have FDA approval for use in patients older than 18 years old, and therefore, the use of these medications in children is considered “off-label.” They may also be difficult to administer in children as none of these medications are offered in liquid or dissolvable wafer form . There are reports of zolpidem abuse among adolescents [27, 28].
Physicians should take into account the half-life of the selective benzodiazepine receptor agonist as it may help them to decide if they want to use it to shorten sleep latency or to increase total sleep time. Zaleplon has a half-life of only 1 h and therefore may be a reasonable choice to use in adolescents with delayed sleep phase disorder as it will shorten sleep latency and will be eliminated well before wake time. It may also lead to decreased side effect of next day sedation. Zolpidem’s half-life is slightly higher at 2.5 h and eszopiclone has a half-life of 6 h.
Hypocretin/Orexin Receptor Antagonist
Suvorexant is the first hypocretin/orexin receptor antagonist to be approved for the treatment of insomnia in adults [29, 30]. Hypocretin/orexin is a neuropeptide that regulates arousal and wakefulness. Mutations and deficits in the hypocretin/orexin system are linked with narcolepsy. The clinical trials in adults found the medication to be effective for insomnia in adults . No studies are available on the safety and efficacy in children.
Antidepressant medications can have sedating properties and have been used for sleep in children in an off-label fashion. Perhaps the most commonly used antidepressant for sleep is trazodone . In the author’s experience (RP), this is not an ideal choice due to unproven efficacy and potential side effects such as anticholinergic effects. An antidepressant approved for adults is doxepin at a low dose of 3 or 6 mg for sleep maintenance insomnia (as opposed to sleep onset) . The author prescribed it to one child with autistic behavior who had disruptive nighttime awakenings but did not have difficulty falling asleep. The family expressed gratitude at the improved sleep. There are no clinical trials in children.
Also, can you add something about the use of atypical antipsychotics? These are also used in children, particularly those with developmental delays.