Clinical manifestations

Presentation and course

	• The acute use of stimulants may cause sudden onset of insomnia.
	• Therapeutic use of CNS stimulants as well as abuse is associated with disordered sleep.
	• Sleep disorders can present during stimulant withdrawal as well.
	• Individuals who abuse stimulants are more likely to have sleep disruption and sleep deprivation.
	• Sleep may be disrupted for months after withdrawal of the stimulants.

Patients with stimulant-dependent sleep disorder may present with divergent sleep symptoms. Typically, patients may note insomnia with stimulant use. However, with stopping of the substance, patients more commonly notice the hypersomnia that is associated with the withdrawal of the substance. Disruption of sleep can occur with therapeutic or recreational use of CNS stimulants. Insomnia most commonly presents at the start of use or when doses are increased. This acute form of insomnia can be easily reversed if doses are reduced, but the continued use of the stimulant may result in the incorporation of other maladaptive habits that further perpetuate the insomnia. Depending on the half-life of the stimulant and the time at which the substance was taken, the patient may note difficulty with sleep onset or sleep continuity. Long-term use of stimulants can produce chronic insomnia. Drug initiation precipitates the insomnia, but other secondary physiological and maladaptive features may perpetuate the insomnia. As individuals note difficulty with attaining refreshing sleep at night, they may have acceleration of the stimulant use to stave off the symptoms of sleep loss. This ever-higher dosing of stimulants would lead to more sleep disruption and a spiraling pattern to the symptoms. Amphetamines may additionally cause disruption of the circadian rhythm leading to irregular sleep-wake patterns. Similarly, the higher doses of any stimulant may lead to further side effects, including racing heart rate, sweating, gastrointestinal upset, and mood changes. Other side effects, such as headache, irritability, nervousness, anorexia, tremor, dyskinesias, and palpitations, may be seen at higher doses of stimulants.

The withdrawal of stimulants is associated with symptoms of excessive sleepiness, irritability, and decreased mood. However, some wake-promoting agents, such as modafinil, rarely produce withdrawal symptoms of fatigue, lethargy, and low mood (28). For those who habitually use caffeine, caffeine withdrawal produces fatigue, headache, decreased alertness, depressed mood, irritability, and difficulty concentrating (37). This may occur after as little as 3 days of caffeine exposure. Amphetamines can also produce rebound sleepiness. The rebound hypersomnia of amphetamines can be sudden and intolerable and, therefore, is often referred to as a “crash.”

Patients who use CNS stimulants under therapeutic guidance appear to have fewer sleep-related abnormalities than those who abuse stimulants. Those who intentionally abuse stimulants may demonstrate variable periods of complete sleep deprivation interspersed with sustained hypersomnia in the withdrawal phase. Chronic stimulant abusers frequently develop psychiatric symptomatology. This may manifest as uninterrupted sleep lasting up to several days. Depression may often be seen during the period of abstinence. Sleep-related withdrawal effects may persist for several months.

Methamphetamine can cause longer-term sleep-wake disruption after as little as a single dose (44). Although many individuals appear to improve their sleep after 4 weeks of abstinence, approximately half of chronic recreational amphetamine users have sleep disruption, including insomnia lasting beyond 4 weeks (03). Amphetamine withdrawal typically produces extended sleep initially, but some chronic users note feeling sluggish for months after.

Cocaine use can mimic that of other stimulants. As cocaine blocks the reuptake of dopamine, norepinephrine, epinephrine, and serotonin, subjects who abuse cocaine report decreased sleep time during the night. These findings correspond with increases in subjective reports of waking early during cocaine maintenance. Conversely, sleep deprivation can increase cocaine-seeking behavior (07). Early studies of cocaine abstinence found that cocaine users had subjective reports of poor sleep and fatigue in the first few days of abstinence, which resolved within 1 to 2 weeks. Prolonged duration of abstinence has been shown to cause a decrease in total sleep time, REM sleep, stages 1 and 2 sleep, and sleep efficiency, with increases in sleep and REM sleep-onset latencies and a slight increase in slow-wave sleep. In contrast, subjective measures of sleep improved over the same period (32). This phenomenon has been described as “occult insomnia” and is postulated to be due to dysregulation of homeostatic sleep drive. Animal studies have shown that these changes may be mediated through an increase in adenosine A2a receptor expression in the hypothalamus (46).

For patients, varied reasons may drive the initial use of stimulants. Some patients presenting with stimulant-dependent sleep disorder may have initially started the stimulant to combat underlying sleepiness. This sleepiness may be from self-induced sleep deprivation or other underlying sleep disorders, such as sleep apnea (11; 12). Although stimulant abuse is uncommon in patients with narcolepsy or other primary hypersomnias (31), individuals may use stimulants to alleviate the symptoms of other disorders producing excessive sleepiness. These patients may not recognize the initial symptoms as a driver for the stimulant use or their connection to their presentation. Some patients may use stimulants for their mood-uplifting features. Stimulants can cause a brief period of elevated mood, and some individuals may seek this to diminish symptoms of depression or to deal with other substance abuse issues (43). Lastly, individuals with underlying fatigue may utilize stimulants to combat their symptoms.

Prognosis and complications

For individuals who are using stimulants under careful medical guidance, the chance of sleep-related symptoms is lower as the dose is controlled and may be adjusted at the presentation of the sleep symptoms. For many individuals with stimulant-dependent sleep disorder, discontinuation of stimulants allows the return to normal sleep-wake patterns. For individuals who abuse stimulants, sleep symptoms are common and may persist for months after stimulant withdrawal. This group is prone to continue to misuse or abuse stimulants on a chronic basis and may develop numerous psychiatric and medical complications in addition to stimulant-dependent sleep disorder (38; 03; 07; 44).

Clinical vignette

A 23-year-old man presented with the chief complaint of “I’m always sleepy if I don’t crank up with ‘meth.’” This young man described excessive daytime sleepiness first developing in his mid-teens. He could recall no precipitating factors accounting for the sleepiness. He indicated that an extensive medical evaluation was completed and that no clear metabolic or systemic cause was found for his somnolence. However, no sleep disorders evaluation was completed at that time.

As the sleepiness began to interfere with his school performance and social interactions, “friends” introduced him to use of illicit stimulants. He described his response as “great, I felt better than normal.” His use of stimulants increased rapidly. He reported that he combined cocaine, methamphetamine, and caffeine tablets in varying combinations and doses every day and night. He indicated “I’d go days with only a couple hours of sleep.” He would “power up” with stimulants for several days with little or no sleep, often filling time with meaningless repetitive tasks. He would then “run out” of stimulants, often sleeping without interruption “for a couple of days.” He was unable to hold a steady job or maintain any lasting friendships. His family finally convinced him to undergo medical detoxification.

He initially had no success with several outpatient-based chemical dependency facilities, quickly relapsing into excessive somnolence and returning to stimulant abuse. He was arrested, tried, convicted, and imprisoned for burglary of a local pharmacy. As an agreement for early release from prison, he was transferred to a locked community-based detoxification halfway house.

A psychiatrist noted the young man’s paroxysmal hypersomnia during group therapy at the detoxification halfway house. As these symptoms persisted for several months, the psychiatrist referred the young man to the sleep disorders center.

Beyond the stimulant-dependent sleep disorder characteristics described above, the young man also had a history of hypersomnia, loud snoring, and witnessed apneas. The patient was noted to have a delayed bedtime and waketime (1:30 AM and 10 AM, respectively). A sleep diary for 2 weeks prior to the sleep studies confirmed the delay in sleep phase.

Despite daily documentation through the detoxification halfway house of several months of abstinence from all drugs and medications, a drug screening test on the day of the sleep study detected residual methamphetamine. The nocturnal polysomnogram demonstrated moderate obstructive sleep apnea that was primarily seen in the supine position. The Multiple Sleep Latency Test (MSLT) revealed an overall mean sleep latency of 4.5 minutes and sleep-onset REM sleep periods in the first two naps (average REM latency 3.5 minutes). Although the diagnosis of narcolepsy was entertained, the presence of REM sleep in the first two naps and the positive urine toxicity screen raised the issue of REM sleep being present in the MSLT due to underlying delayed sleep phase and the withdrawal of an REM-suppressant stimulant substance.

The patient was subsequently treated with an oral appliance, which showed resolution of the sleep apnea. His daytime sleepiness persisted, and he was started on modafinil and was titrated to a dose of 400 mg daily. He noted improvement, and he remained free of recreational drug use over the next several months while still at the halfway house. This positive response continued over most of the following year while training at a community outreach employment setting.

Biological basis

Etiology and pathogenesis

	• Stimulants work through a variety of mechanisms to improve alertness.
	• Many CNS stimulants release and block the reuptake of norepinephrine, dopamine, epinephrine, and serotonin in the CNS.
	• Caffeine acts as an antagonist to adenosine receptors blocking the homeostatic drive for sleep and may have secondary effects on dopamine.
	• The stimulant, pitolisant, appears to work through increasing histamine and possibly noradrenergic neuron activity.
	• Genetic variations and other factors may influence the individual response to CNS stimulants.
	• Tolerance and rebound are most pronounced with these agents in stimulant-dependent sleep disorder.

Sleep disorders associated with CNS stimulants are listed in Table 1.

Table 1. Sleep Disorders Associated with CNS Stimulants

Insomnia
	• amphetamines: dextroamphetamine • methylphenidate • caffeine • donepezil • cocaine • dopaminergic agents • ephedrine • modafinil / armodafinil • monoamine oxidase inhibitors • nicotine • pemoline • pitolisant • selective serotonin reuptake inhibitors • solriamfetol • tricyclic antidepressants
Obstructive sleep apnea
	• Recreational drugs, eg, methylenedioxymethamphetamine
Excessive daytime sleepiness
	• Withdrawal of CNS stimulant medications • Secondary to CNS stimulant-induced insomnia at night
Vivid dreams and nightmares
	• amphetamines • methylphenidate • phenmetrazine
Source: Modified from (24)

The pathogenesis and pathophysiology of stimulant-dependent sleep disorder is not well established. Preexistent psychiatric illness may also predispose to stimulant-adverse reactions, including stimulant-dependent sleep disorder. Tolerance to stimulant effects and rebound hypersomnia may be contributing factors. What is clear is that stimulants can broadly influence sleep by increasing the total time that a person is awake at night and the number of arousals during the sleep period, culminating into sleep fragmentation and sleep deprivation. Some stimulants, especially those that increase serotonin or norepinephrine, appear to decrease REM sleep. However, the relative impact of this is unknown and requires further investigation. Withdrawal of stimulants frequently results in a rebound of both NREM and REM sleep. The remaining portion of this section is devoted to the mechanisms of common stimulants.

The most common category of stimulants involved in stimulant-dependent sleep disorder is indirect sympathomimetics. Amphetamine, cocaine, and methylphenidate all enhance the release and block the reuptake of norepinephrine, dopamine, and serotonin in the CNS. The most important effects of these types of stimulants are on the dopaminergic systems, but the norepinephrine system also contributes to subjective effects. Tolerance and rebound are most pronounced with these agents in stimulant-dependent sleep disorder.

Methylphenidate is one of the more widely prescribed stimulants for learning disabilities. As the rate of these prescriptions rise, side effects are more prevalent. Insomnia is a recognized side effect of methylphenidate used for the treatment of attention deficit hyperactivity disorder (ADHD) in children. The relationship between the drug and sleep is complex (05). Variables that influence the results of various studies on this topic include differences in the pharmacokinetics of methylphenidate formulations such as oral extended-release, and osmotic-release preparations as well as transdermal systems. Effects on sleep vary according to dose and duration of therapy as well as sleep problems as part of ADHD prior to start of therapy. In clinical trials, insomnia has been reported to be increased in children with attention deficit hyperactivity disorder who are receiving the CNS stimulant methylphenidate as compared to children in the placebo group. Dose-response effects of extended-release dexmethylphenidate and extended-release mixed amphetamine salts on objective measures of sleep were studied in an 8-week, double-blind, placebo-controlled, randomized, crossover study of youth with attention deficit hyperactivity disorder (39). A systematic review of randomized trials of methylphenidate for attention deficit hyperactivity disorder in adolescents and children showed that those in the methylphenidate group were at a 60% greater risk for trouble sleeping and sleep problems as compared to the placebo group (40). A meta-analysis of various studies of stimulant medications for attention deficit hyperactivity disorder showed longer sleep latency, worse sleep efficiency, and shorter sleep duration as adverse effects, particularly in the young patients (26). Insomnia is prevalent in adult ADHD and is related to higher severity of the disorder as well as psychiatric and medical comorbidities, but outcomes of insomnia disorder can be improved by stable pharmacological ADHD treatment, with careful use of stimulants (18).

Pemoline is a CNS stimulant but is structurally different from amphetamines and methylphenidate. Tolerance and rebound are extremely rare with use of pemoline in stimulant-dependent sleep disorder dependence. This medication is no longer prescribed in the United States.

Modafinil and armodafinil, the R-enantiomer of modafinil, act selectively in areas of the brain believed to regulate normal wakefulness. Compared to modafinil, armodafinil has a longer half-life and better wakefulness effects. This selective CNS activity is distinct from the action of amphetamine and methylphenidate. Modafinil increases daytime wakefulness but does not interfere with the integrity or architecture of nighttime sleep. In a pilot study on human volunteers, modafinil blocked dopamine transporters and increased dopamine in the human brain, including the nucleus accumbens, indicating the potential for development of drug abuse and drug dependence in vulnerable persons (45). Overall, modafinil appears to be a weak dopamine reuptake inhibitor. Although it has minimal binding to serotonin or norepinephrine transporters, the medication is associated with producing elevated levels of norepinephrine and serotonin in the prefrontal cortex (19). Additional evidence suggests that modafinil may increase hypothalamic histamine and orexin signaling (23). The United States Army uses modafinil as a replacement for dextroamphetamine for sustaining alertness in military helicopter pilots as it maintains alertness and situational awareness of sleep-deprived aviators consistently better than placebo and without side effects of aeromedical concern (17).

Pitolisant is a wake-promoting agent approved for use in patients with narcolepsy and the residual sleepiness of obstructive sleep apnea. This agent primarily works through increasing histamine by acting as a H3R antagonist/inverse agonist. In animal studies, the drug does not show the same amphetamine-like behaviors seen with other psychostimulants (27). The medication may interact with other monoamine acting agents and, thus, should not be started with SSRIs or SNRIs. Insomnia, headache, and gastrointestinal symptoms are noted side effects. Solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor, has been approved by the FDA for the reduction of sleepiness and improvement of wakefulness in patients with narcolepsy and obstructive sleep apnea. This agent also appears to increase dopamine in the nucleus accumbens (27). Unlike stimulants like methylphenidate or dextroamphetamine, it does not have rebound hypersomnia or withdrawal effects. However, insomnia is listed as an adverse effect in some clinical trials (41). Because the duration of action of the drug is approximately 9 hours, the drug is recommended to be taken soon after awakening to reduce the side effect of insomnia.

Donepezil is commonly used to combat the cognitive decline associated with a variety of dementias. This medication primarily works by inhibiting the degradation of acetylcholine, thereby promoting alertness. This agent is associated with a decrease in total sleep time at night and prolongation of sleep latency (04). Donepezil is also associated with nightmares.

Nicotine administered as a transdermal patch in nonsmokers can cause disruption of the sleep architecture. The mechanism of action is primarily through the nicotinic acetylcholine receptors in the brain, but there also appears to be some stimulation of the dopamine system in the nucleus accumbens (42). As these patches are used both day and night to suppress the nicotine craving, they also produce insomnia and sleep disruption.

Caffeine blocks adenosine binding and impairs adenosine from contributing to the homeostatic sleep drive in the hypothalamus. Despite caffeine’s relatively short blood half-life of 2.5 to 5 hours, caffeine may have much longer effects. Part of this may be related to the principle active metabolite of paraxanthine peaking 7 to 8 hours after caffeine administration. The secondary effect of these compounds on the brain may outlast 36 hours (30). Although the relationship between coffee and sleep is not straightforward, caffeine can prolong latency to sleep onset and decrease total sleep, even at relatively low doses (36). Even higher doses in caffeine-adapted individuals may have an effect. A study has shown that 400 mg of caffeine taken 6 hours before bedtime has important disruptive effects on sleep (16). This effect may have several features that influence the degree of impact from caffeine. Age, underlying degree of slow-wave sleep, and genetics may play a role. Reichert found that the greater the initial percentage of slow-wave sleep, the more impact caffeine had on disrupting sleep (36). Given the relationship of slow-wave sleep to age, this may account for a portion of the age effect. In another study, a significant effect of sleep duration was change in tendency of caffeine use. Hu found that a shorter sleep duration predicted a stronger tendency to consume caffeine, but this phenomenon was only found in middle-aged adults and not in older adults (22). Caffeine may also influence the circadian rhythm. A study has shown that evening caffeine consumption delays the human circadian melatonin rhythm, which affects the sleep-wake cycle primarily based on an adenosine receptor/cyclic adenosine monophosphate-dependent mechanism (09). Thus, caffeine may affect both the homeostatic and circadian drivers of sleep.

Genetics appear to play a role in individual variability in the metabolism and effects of caffeine. Both pharmacodynamic and pharmacokinetic polymorphisms have been linked to variation in response to caffeine (47). The common genetic variation of ADORA2A is an important determinant of psychomotor vigilance in the rested and sleep-deprived state and modulates individual responses to caffeine after sleep deprivation (08). A genome-wide study confirmed the association with a polymorphism in the ADORA2A gene and discovered several genes influencing caffeine-induced insomnia, including an intergenic single nucleotide polymorphism near the GBP4 gene on chromosome 1 (10). These findings demonstrate a role for adenosine A2A receptors in the effects of prolonged wakefulness on vigilant attention and sleep EEG. A2A receptors, as well as dopamine transporters, contribute to individual differences in impaired sleep quality induced by caffeine and caffeine sensitivity.

Like amphetamine, cocaine use has the similar effects of reducing REM sleep and increasing latency to REM sleep. Withdrawal from cocaine results in REM sleep rebound and reduced latency to REM sleep. Experimental evidence indicates that blockade of dopamine transporter increases extracellular dopamine, a wake-promoting neurotransmitter. The increased arousal and sleep disruption following cocaine use may influence the risk of relapse because the behavioral effects of cocaine are highly correlated with inhibition of dopamine transporter (06).

Epidemiology

The incidence and prevalence of stimulant-dependent sleep disorder are not known. Small studies suggest that individuals who are not on stimulants as part of a treatment paradigm for specific symptoms are more likely to develop stimulant-dependent sleep issues, but further studies are needed. Caffeine causing insomnia, however, appears to be strongly associated with shorter sleep and complaints of insomnia (12).

Prevention

No large studies have been performed regarding the prevention of stimulant-dependent sleep disorder. In view of the frequent use of caffeine and its disruptive effect on sleep, patients should generally be counseled to avoid caffeine, especially after the mid-day meal. Some additional clinical strategies may help to reduce the development of stimulant-dependent sleep disorder. As with any medication, the goals, risks, side effects, and benefits of the use of stimulants should be reviewed and agreed on between the practitioner and the patient. Emphasis on good sleep hygiene and nonpharmacological therapies in treating underlying symptoms is important. The practitioner should set realistic goals for treatment to foster reasonable expectations before starting the stimulants. For many hypersomnias, treatment will not resolve the sleepiness completely, and medication doses should not be escalated to attain this result. The physician should consider starting stimulant treatment at the lowest effective dose and titrating to clinical response and safety. Use of laboratory monitoring, such as multiple sleep latency testing or maintenance of wakefulness testing, may assist in titrating doses. Therapeutic drug monitoring may be used to ensure that serum drug levels do not exceed the upper limit of the normal range. The physician should also encourage counseling and long-term support with regional or national support groups.

Prior to the use of stimulants in children, attention should be given to the possibility that daytime symptoms, such as irritability or attention issues, may be related to sleep issues. Symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents have been attributed to sleep problems, and screening for sleep problems is recommended before initiating medication for ADHD. Because treatment of ADHD with stimulants may disrupt sleep, it is recommended that health care professionals ensure that a child is obtaining adequate sleep before being placed on stimulants (21).

Differential diagnosis

Confusing conditions

Stimulant-dependent sleep disorder must be differentiated from that due to substance abuse. The insomnia symptoms during stimulant use may be confused with:

	• psychophysiologic insomnia
	• anxiety-related insomnia
	• disorders of initiating and maintaining sleep

Associated or underlying disorders

Hypersomnia during stimulant withdrawal must be differentiated from other causes of excessive daytime sleepiness such as:

	• Narcolepsy
	• Sleep apnea
	• Idiopathic hypersomnia
	• Hypersomnia due to a medical disorder
	• Behavioral/sleep insufficiency
	• Fatigue

Psychiatric symptoms, such as insomnia irritability and sleep disruption, that can present with stimulant use must be differentiated from preexistent or comorbid primary psychiatric disorders.

Patients with ADHD frequently have insomnia and daytime sleepiness, and adverse effects of CNS stimulant therapy should be evaluated against this background.

Diagnostic workup

	• Thorough history
	• Drug screening of blood and urine
	• Polysomnography if sleep apnea or related movement disorders are suspected.

Stimulant-dependent sleep disorder is found with a thorough history and possibly a drug screen. As with all sleep complaints, detailed sleep, medical, and psychiatric histories are the most significant initial diagnostic steps. Drug screening of blood and urine for metabolites as biomarkers of stimulants, sedative-hypnotics, anxiolytics, or other drugs of abuse are important diagnostic procedures in stimulant-dependent sleep disorder. If there is a concern for underlying sleep disorders, such as sleep apnea or primary hypersomnia, polysomnographic evaluation followed by Multiple Sleep Latency Test should be performed after at least 2 weeks of documented abstinence from stimulants.

Management

	• Focus on understanding the underlying reason for the start of stimulant use and the patient’s goals and fears.
	• Gradual withdrawal of the stimulant may provide easier transition.
	• Prevention is most important in the management of CNS stimulant associated sleep disorders.
	• There is no routine treatment, but a comprehensive approach is required including that for drug abuse and withdrawal and not just sleep disorder.

When considering the secondary effects of a medication, such as a stimulant, the practitioner may find important treatment issues when accounting for the original symptoms and drivers for stimulant use. Similarly, asking for the patient’s goals may provide insight to key areas that need to be addressed in order for the stimulant withdrawal to be successful. Patients may have a variety of concerns, fears, and misconceptions that will need to be addressed as part of the therapy goals. For stimulant misuse and abuse, a team approach to a comprehensive drug withdrawal program will be a key asset for success.

For common stimulant use, such as caffeine, a gradual weaning may be a reasonable strategy. Decreasing any caffeine consumed later in the day may be an easier approach for patients to start with. Patients should be warned about the symptoms of caffeine withdrawal, such as headache and fatigue, as this may indicate a slower taper schedule may be needed. Additionally, the patient may not note the beneficial effects of being caffeine free for 3 to 4 weeks after stopping caffeine.

Some pharmacologic agents may be beneficial for the treatment of stimulant-dependent sleep disorder. A meta-analysis of literature as well as clinical studies indicate that melatonin is safe and effective in improving sleep in children with neurodevelopmental disorders (01). This study included children with sleep disorders related to treatment with stimulants. Management of drug abuse requires more comprehensive efforts rather than just a focus on sleep disorders.

Amphetamine-type stimulants-use disorders result from prolonged use of highly addictive synthetic amphetamines, and multiple symptoms include insomnia. There is no satisfactory treatment for these disorders, but cognitive behavioral treatment is used widely. A systematic review of randomized trials comparing cognitive behavioral treatment with other treatments for amphetamine-type stimulants-use disorders revealed only two trials that met the selection criteria, and there was insufficient evidence for the efficacy of cognitive behavioral treatment (20).

There is no routine or well-established treatment for symptoms of stimulant withdrawal. Depression is often seen during the withdrawal period, and antidepressant medication may be helpful. Those who intentionally abuse stimulants and who present with stimulant-dependent sleep disorder have usually been treated with psychological and psychosocial approaches. Chemical dependency treatments, both in the inpatient and outpatient settings, have been successful. Modafinil has been prescribed to treat withdrawal symptoms of methamphetamine. Modafinil has also shown to normalize the effects on sleep from cocaine abstinence in chronic users (34). Findings of a randomized, double-blind, placebo-controlled, crossover clinical trial suggest that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently (15). This strategy of “trading down” can help ease the psychological dependence of needing something and may promote buy-in from more resistant patients.

Long-term use of CNS stimulant medications can improve attention, working memory, and learning but results in poor sleep. A study has shown that longer duration of sleep at baseline is related to enhanced attention and has emphasized the importance of evaluating and monitoring sleep when prescribing stimulant medication for ADHD in children (33). Appropriate measures should be taken to improve stimulant-induced sleep disorder in these children. If delay in onset of sleep or insomnia persists after use of an effective ADHD treatment, alternative dosages as well as formulations, and timing of administration of medications should be considered for optimal benefit during the day without compromising sleep (13). Among various pharmacological treatments, randomized clinical trials support the use of melatonin to reduce sleep-onset delay, as compared to other medications with more limited evidence. Influencing the adrenergic effect may influence sleep. Clonidine, a nonselective alpha-2 adrenergic agonist used for the treatment of hypertension, has a synergistic effect with CNS stimulants and is approved as an add-on or second-line treatment for ADHD. It is particularly useful for the management of sleep initiation latency and night awakening as well as CNS stimulant-induced sleep disorder in ADHD (35). However, it does not appear that other pharmacological agents may help. Findings of a randomized, double-blinded, placebo-controlled clinical trial showed that cyproheptadine, an antihistamine that induces drowsiness as a side effect, does not have any significant preventive effect on sleep disorders caused by methylphenidate in children with ADHD (25).

Another approach to reduce adverse effects of CNS stimulants is to switch to the use of pitolisant for the treatment of narcolepsy. Pitolisant acts on histamine three receptors to activate histamine release in the brain and enhances wakefulness. Clinical studies have shown that pitolisant significantly decreases excessive daytime sleepiness and cataplexy rate versus placebo and is well tolerated (29). However, insomnia has been reported as a side effect. A long-term study has confirmed safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis (14).

Special considerations

Pregnancy

CNS stimulant use should be avoided in pregnancy because of possible adverse effects on the fetus. Pre-pregnancy counseling and therapy should be advised. Women of childbearing age should be given folate to reduce the general risk of fetal malformation.

Anesthesia

Specific information is not available but cross-tolerance or additive effects may be present, precluding a combination of stimulants and anesthetic agents. Concerns have been raised about sodium oxybate interactions with benzodiazepines and anesthetic agents.