Positive routines involve the parents developing a set bedtime routine characterized by quiet activities that the child enjoys. Faded bedtime with response cost involves taking the child out of bed for prescribed periods of time when the child does not fall asleep. Bedtime is also delayed to ensure rapid sleep initiation and that appropriate cues for sleep onset are paired with positive parent-child interactions. Once the behavioral chain is well established and the child is falling asleep quickly, the bedtime is moved earlier by 15–30 min over successive nights until a preestablished bedtime goal is achieved.

Extinction has been found to be an effective intervention for sleep problems in infants and very young children [87].

In fact, most behavioral methods for treating sleep problems in these age groups incorporate principles of extinction. Extinction is based on the hypothesis that night wakings and attention-seeking behaviors are positively reinforced by parental attention and other behaviors. Thus, extinction involves parents helping their children to establish self-soothing skills (e.g., parents are told to put their infants to bed drowsy, but not asleep, which helps the child learn to settle to sleep on his/her own). The parent is not to respond to their child’s attempts at reengaging the parent to provide external soothing techniques (e.g., feeding, rocking, singing). The goal is for the child to learn to self-soothe.

The biggest obstacle associated with extinction is lack of parental consistency. Parents must ignore their child’s cries every night, no matter how long it lasts. Many parents are unable to ignore crying long enough for the procedure to be effective.

Tikotzky and Sadeh [87] reported that it can be helpful and encouraging to inform parents that research has not found that limiting parental involvement in order to promote self-soothing results in adverse effects on the infant’s emotional well-being or on the parent-child relationship. The child is placed in bed while awake, left alone until asleep, and night wakings are ignored. The infant learns to self-soothe once realizing that nighttime crying does not result in parental attention.

If parents respond after a certain amount of time, the child will only learn to cry longer the next time. Parents are also instructed that post-extinction response bursts may occur. That is, often at some later date, there is a return of the original problematic behavior. Parents are instructed to avoid inadvertently reinforcing this inappropriate behavior following such an extinction burst. The common term used in the media and self-help books to describe unmodified extinction techniques is the “cry it out” approach.

For parents who are opposed to unmodified extinction, other variants of extinction, such as graduated extinction or parental presence extinction, may be a better intervention alternative. Graduated extinction involves parents ignoring disruptive bedtime behaviors for a predetermined period. If the child has not settled at the end of that time, the parent settles the child back in bed, but minimizes interaction with the child. Extinction with parental presence involves the parent lying down in a separate bed in the infant’s room during settling and awakening. Parents feign sleep and do not attend to the infant directly. Parents follow this procedure for 1 week, after which they follow an unmodified extinction procedure. This technique has been found to reduce the extinction burst (increase in signaling behaviors) that is typically seen when using unmodified extinction. This involves ignoring negative behaviors (i.e., crying) for a given amount of time before checking on the child. The parent gradually increases the amount of time between crying and parental response. Parents provide reassurance through their presence for short durations and with minimal interaction.

Either parents can employ a fixed schedule (e.g., every 5 min), or they can wait progressively longer intervals (e.g., 5 min, 10 min, then 15 min) before checking on their child. With incremental graduated extinction, the intervals increase across successive checks within the same night or across successive nights. The checking procedure itself involves the parents comforting their child for a brief period, usually 15 s to a minute. The parents are instructed to minimize interactions during check-ins that may reinforce their child’s attention-seeking behavior.

The goal of graduated extinction is to enable a child to develop “self-soothing” skills in order for the child to fall asleep independently without undesirable sleep associations (e.g., nursing, drinking from a bottle, rocking by parent). Once these skills are established, the child should be able to independently fall asleep at bedtime and return to sleep following normal nighttime arousals.

Scheduled awakening entails establishing a baseline of the number and timing of spontaneous night wakings. Then a preemptive waking schedule wherein parents awaken their child approximately 15–30 min before typical spontaneous night waking is implemented. As the treatment progresses, the time between scheduled awakenings is increased until eventually there are no awakenings. When parents awaken the child, they are instructed to engage in their typical behaviors (e.g., feeding, rocking, soothing) as if the child had awakened spontaneously.

Scheduled awakenings appear to increase the duration of consolidated sleep, but the mechanisms behind why this intervention decreases nighttime awakenings are not well understood. Scheduled awakenings are a treatment option for frequent nighttime awakenings, but are not appropriate for problems with sleep initiation. Also, compared to extinction, it can be more complicated to carry out and may take several weeks rather than days before improvements are seen.

Faded bedtime, often used in combination with sleep hygiene, involves determining a time at which it is likely the child will fall asleep within about 15 min of going to bed [88].

Once the child falls asleep at this time with little resistance, the bedtime is set earlier after a series of successful nights until the desired bedtime is achieved. Also, the child’s wake time is set at the same time each day, and the child is not allowed to sleep outside the prescribed sleep times. A modified version of this technique, faded bedtime with response cost, involves bedtime fading, as described above. However, if the child does not fall asleep within a certain period of time, the child is removed from bed (response cost) to decrease the negative association between being in bed and awake and to increase the likelihood that the child will fall asleep. After a predetermined time (typically about 30 min during which time the child engages in a non-arousing activity), the child returns to bed. This procedure is repeated until the child falls asleep. Once successful at the target bedtime, an earlier bedtime is set as the goal. The aims of the treatment are in line with the goals of extinction: to increase appropriate behaviors and positive associations with sleep and to decrease arousal by helping the child to develop self-soothing skills and fall asleep independently. This technique involves delaying bedtime closer to the child’s target bedtime. The goal of this treatment is for the child to develop a positive association between being in bed and falling asleep rapidly. Bedtimes can be gradually moved earlier.

It should be taken into account that the long-term efficacy of behavioral treatment is not completely assessed: a systematic review, although acknowledging the efficacy in short term, reported finally that moderate-level evidence supports behavioral interventions for pediatric insomnia in young children and even low evidence in adolescents and in children with neurodevelopmental disabilities. This review showed that only four studies assessed sleep-onset latency, with a significant overall effect and small to medium effect size at posttreatment. Also the evaluation of the efficacy on the frequency of night wakings (seven studies), and on the night waking duration (four studies), resulted in a significant effect but with a small to medium effect size. Finally, a nonsignificant overall effect on night wakings was found at 3–12-month follow-up across five studies [89].

Following the results of this study, we should reconsider the claimed “efficacy” of behavioral interventions; more studies are needed to identify factors that may predict treatment success and to tailor behavioral interventions for young children based on child (e.g., temperament, age), parental, and environmental factors [86]. Finally, more longitudinal studies are needed to demonstrate whether treatment benefits for insomnia are maintained over time and to examine other functional outcomes (child mood, behavior, health, as well as parental mood, marital satisfaction, and family functioning).

For waiting times in case of nocturnal awakenings, follow those indications:

Tryptophan is a precursor of serotonin and melatonin widely used in the 1980s for treatment of sleep disorders and headache prophylaxis. It does not have opioid-like effects and does not limit cognitive performance or inhibit arousal from sleep [96]. In the literature, several positive effects on sleep are reported: improvement of sleep latency [97–99].

The exact mechanism of action of the sedative effects of L-tryptophan is unknown, but the effect is not mediated by the conversion in serotonin.

5-HTP is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. 5-HTP is not found in the foods and eating foods with tryptophan slightly increases 5-HTP levels. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. The effects of 5-HTP on sleep structure are conflicting: increase or decrease of REM and increase of SWS [100].

In 1989, the presence of a contaminant called Peak X was found in tryptophan supplements that could determine eosinophilia-myalgia syndrome (EMS); however, a recent study reported that there is no evidence to implement 5-HTP intake as a cause of any illness, especially the EMS or its related disorders [101].

Very limited data are available on the effects of 5-HTP on insomnia symptoms.

There is clear evidence of therapeutical effect for sleep terrors in children at dosage of 2 mg/kg [92, 93].

Histamine is a wake-promoting neurotransmitter, and inactivation or suppression in various animal models has led to sedation and disrupted wakefulness patterns [102].

The first generations of antihistamines are lipid soluble and pass through the blood-brain barrier; they bind to H1 receptors in the CNS and have minimal effects on sleep architecture. They are often the more acceptable choice for many families, commonly well tolerated, and may acutely improve sleep and speed up behavioral programs.

These agents may worsen obstructive sleep apnea (OSA), and also may suppress rapid eye movement (REM) sleep [90].

Diphenhydramine is the most commonly used and is a competitive H1-histamine receptor blocker. Peak blood and tissue levels are achieved within 2 h of ingestion. The recommended dosage for adults is 25–50 mg, whereas in children the effective dose is between 0.5 mg/kg and 25 mg. A study showed a significant decrease in sleep latency time and number of awakenings [103], while other studies reported no more effectiveness than placebo [104, 105].

Very few studies have been conducted with other antihistamines in children with insomnia, reporting conflicting results. Trimeprazine was used in 22 children with night wakings showing a moderate improvement [106]; niaprazine showed a decrease of sleep-onset latency and an increase of sleep duration [107] even if compared with benzodiazepines [108].

The most common adverse reaction to antihistamines at therapeutic doses is impaired consciousness. The predominant features in an overdose are anticholinergic effects, including fever, blurred vision, dry mouth, constipation, urinary retention, tachycardia, dystonia, and confusion.

Melatonin (N-acetyl-5-methoxytryptamine) is a chronobiotic drug crucial for the regulation of the sleep/wake cycle. In older children and adults, its production and secretion begin in the evening and peak during the night between 2:00 and 4:00 AM; its production and release are inhibited by light. There is now a greater understanding that low doses (0.5 mg) can be effective for some children, with diminishing benefit with doses exceeding 6 mg, and unlike traditional hypnotics such as chloral hydrate and the benzodiazepines, melatonin does not affect sleep architecture [24].

In general MLT for treatment of chronic sleep-onset insomnia in children is effective in a dosage of 0.05 mg/kg given at least 1–2 h before desired bedtime [109].

Systematic reviews and meta-analyses of placebo-controlled, randomized controlled trials (RCTs) in children with neurodevelopmental disabilities, especially autism, have demonstrated that exogenous melatonin improves sleep, either by reducing the time taken to fall asleep (sleep-onset latency) or by increasing total sleep time (sleep maintenance and sleep efficiency), or both [110, 111].

Further, MLT at a dosage of 5 mg was effective in ADHD children with delayed sleep-phase syndrome (DSPS) and insomnia [112–115].

These effects have been also observed in typically developing children with delayed sleep-phase syndrome.

Melatonin is increasingly prescribed to many children using a wide range of doses, demonstrating efficacy in improving sleep quality, by reducing sleep-onset latency or slightly increasing total sleep time.

A large clinical trial confirmed the efficacy of melatonin in the treatment of sleep impairment in children with NDDs, using different doses, ranging from 0.5 to 12 mg; the main effects of melatonin were reduced sleep latency (from 102 to 55 min in 12 weeks) and increased total sleep time (40 min) [116].

Headaches, confusion, dizziness, cough, and rashes have been reported, but these are common symptoms in children and are likely to be coincidental or caused by impurities in the many imported and often unregulated formulations of melatonin. Previous reports of poor seizure control, poor asthma control, and adverse endocrinological problems during puberty have not been confirmed. The systematic reviews and meta-analyses of RCTs all suggest that there are no significant adverse side effects associated with the use of melatonin [24].

Further research is required to evaluate the metabolism of melatonin, the function of its receptors, and its value in specific neurodevelopmental disorders. Unanswered clinical questions include whether slow-release preparations are superior to immediate-release in increasing total sleep time, and whether a more rational and optimal prescription of melatonin might be achieved by measuring salivary melatonin before its use.

Iron is a cofactor for tyrosine hydroxylase, the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dopamine.

Iron deficiency anemia was reported to be associated with higher motor activity during sleep, shorter night sleep duration, and higher frequency of night waking [117], and supplemental iron was associated with longer sleep duration [118].

In some cases, night awakenings starting in the first year of life might be an early sign of restless legs syndrome [119, 120].

This kind of insomnia with motor hyperactivity and characterized by awakening after 1–3 h of sleep followed by screaming, crying, kicking, and slapping the legs or by verbally expressing that the legs “hurt” with a seemingly comforting effect of massage and cycling movements performed by the parents is reported to be related to low serum ferritin level [67].

Because iron deficiency is common in children, measuring the ferritin level is reasonable. Iron replacement should be initiated if ferritin levels are less than 50 mcg per L, and they should be rechecked in 3 months [121]; although the risk of iron overload is very low, parents should be asked for a personal and family history of hemochromatosis or unexplained liver disease.

Clinical research on the relation between vitamin D and sleep is ongoing, and few studies have been published on the role of vitamin D metabolism and sleep disorders. Preliminary data suggest the possibility that altered vitamin D metabolism could play an important role in the presentation and severity of sleep disorders [122]. Vitamin D is related to dopamine metabolism; it could be useful to investigate vitamin levels in association with iron parameters in children with motor hyperactivity during sleep.

Clonidine is a central α₂ agonist that has been widely used in treating sleep disturbances (mainly sleep-onset delay) in children with ADHD [123].

Clonidine is rapidly absorbed and has onset of action within 1 h and peak effects in 2–4 h. Starting dose is usually 50 μg, increased in 50 μg increments.

Tolerance to the sedating effects may develop with sedative effects tending to decrease over time, thus necessitating gradual increases in dose and associated increased potential for adverse effects.

No randomized trials of clonidine specifically for children with insomnia exist, but the few studies showed a certain efficacy on sleep latency and night wakings. Side effects include hypotension, bradycardia, irritability, anticholinergic effects (e.g., dry mouth), and REM suppression [124].

Benzodiazepines bind to the benzodiazepine subunit of the gamma aminobutyric acid (GABA) chloride receptor complex, facilitating the action of the inhibitory neurotransmitter GABA. These hypnotics have long been the first-choice treatment for insomnia in adults, but raise concerns about cognitive impairment, rebound insomnia, and the potential risk for dependence. These concerns, and little evidence-based data availability in the pediatric population, contribute to limit their use in children [125]. Possible side effects include daytime sedation, hypotonia, rebound insomnia on discontinuation, psychomotor/cognitive impairment, and impairment of respiratory function [126].

It is a non-benzodiazepine receptor agonist (NBzRA) that binds preferentially to GABA_A receptor complexes containing α₁ subunits; it has minimal effects on sleep architecture with a slight increase to slow-wave sleep [127].