Clinical manifestations

Presentation and course

	• Therapeutic use of CNS stimulants as well as abuse is associated with sleep disorder.
	• Sleep disorders are associated with CNS withdrawal as well.

Stimulant-dependent sleep disorder is seen not only after therapeutic use of CNS stimulants, but with their abuse as well. In the former case, insomnia may result when stimulant treatment is started or the medication dose or schedule is changed. Withdrawal symptoms of excessive sleepiness and irritability may develop if stimulants are abruptly discontinued. Other side effects such as headache, irritability, nervousness, anorexia, mydriasis, tremor, dyskinesias, and palpitations may be seen during use of the stimulants. The occurrence of side effects is higher in those who exceed the recommended dosages.

Subjects who abuse cocaine report decreased sleep time, which is noted to be largely due to decreased sleep time during the day, but there is a small and significant decrease in sleep time during the night. These findings correspond with increases in subjective reports of waking early during cocaine maintenance. There is an increase in NREM sleep and a decrease in REM sleep in active users. During the first week of cocaine withdrawal, there is a decrease in REM sleep latency, REM sleep percentage, and REM density increase, and total sleep time increases. 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-onset latencies and a slight increase in slow-wave sleep. In contrast, subjective measures of sleep improved over the same period (23). 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 (32).

Amphetamine withdrawal induces significant rebound hypersomnolence (increased sleep following increased wakefulness). The rebound hypersomnia of amphetamine is sudden and intolerable and, therefore, often referred to as a crash. Some of the other wake-promoting agents, such as modafinil and caffeine, do not cause rebound hypersomnia. The basic mechanism of stimulant-induced rebound hypersomnia is not well explained. One explanation is that rebound hypersomnia is mediated through dopamine release and is not associated with dopamine transporter antagonism (14).

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. However, repeated polysomnographic studies during stimulant withdrawal reveal a more complex effect on sleep and wakefulness. After the first 7 to 10 days, acute hypersomnia and REM sleep rebound reverses. More disrupted sleep with relatively reduced total sleep time and reduced REM sleep develops in the subacute phase through 2 to 3 weeks. Therapeutic use of CNS stimulants produces fewer sleep-related abnormalities than abuse of stimulants.

Prognosis and complications

Many individuals with stimulant-dependent sleep disorder may discontinue stimulants and return to normal sleep/wake patterns. However, others continue to misuse or abuse stimulants on a chronic basis. The latter group may develop numerous psychiatric and medical complications in addition to stimulant-dependent sleep disorder.

Clinical vignette

A 23-year-old man presented with the chief complaint of Im always sleepy if I dont 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 Id 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 mans 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 paroxysmal hypersomnia, frequent episodes of sleep paralysis, and episodes strongly suggestive of cataplexy, prior to stimulant abuse. As there was ample daily documentation through the detoxification halfway house of several months of abstinence from all drugs and medications, a polysomnographic evaluation was completed, immediately followed by multiple sleep latency testing. Drug screening before the tests did not detect drugs or metabolites of drugs of abuse or of prescription medication.

The nocturnal polysomnogram was unremarkable, save for an early first REM period (REM latency 14 minutes). The Multiple Sleep Latency Test revealed 5 sleep-onset REM periods in 5 naps (average REM latency 3.5 minutes) and an overall mean sleep latency of 1.5 minutes. Narcolepsy was diagnosed; subsequent testing also demonstrated presence of HLA DQB1*0602. He was started on modafinil and was titrated to a dose of 400 mg daily. He described his response as remarkable and he continued doing well 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. He advanced to a supervisory position and maintained control of excessive daytime somnolence on the 400 mg daily dose of modafinil alone, through 18 months of follow-up.

However, he met up with former friends and, according to family members, he, again, dropped out and was abusing stimulants. He was lost to further follow-up.

Biological basis

Etiology and pathogenesis

	• CNS stimulants release and block the reuptake of norepinephrine, dopamine, and serotonin in the CNS.
	• 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 • Cocaine • Dopaminergic agents • Ephedrine • Modafinil • Monoamine oxidase inhibitors • Nicotine • Pemoline • 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 (18)

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.

Although 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. 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. 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 (13).

Pemoline is a CNS stimulant but is structurally different from to amphetamines and methylphenidate. Tolerance and rebound are extremely rare with use of pemoline in stimulant-dependent sleep disorder dependence.

Modafinil acts selectively in areas of the brain believed to regulate normal wakefulness. 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 (31). The United States Army uses modafinil as a replacement for dextroamphetamine for sustaining alertness in military helicopter pilots as it maintains alertness and situation awareness of sleep-deprived aviators consistently better than placebo and without side effects of aeromedical concern (12).

Sodium oxybate, when used properly to treat daytime sleepiness associated with narcolepsy, is less likely to lead to the development of tolerance and other undesirable side effects. However, due to the known drug abuse of sodium oxybate, the approval of this drug in the United States is contingent on a risk management plan that restricts distribution through a single central pharmacy and requires use of a specific prescription form.

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. 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 (30). Because the duration of action of the drug is approximately 9 hours, insomnia is likely to occur if the drug is taken later in the day.

Armodafinil is a prescription medicine used to treat the symptoms of obstructive sleep apnea, narcolepsy, and shift work sleep disorder. It is a R-enantiomer of modafinil. Compared to modafinil, armodafinil has a longer half-life and better wakefulness effects; both drugs have the same incidence of insomnia as a side effect, ie, 5%.

Nicotine administered as a transdermal patch in nonsmokers can cause disruption of the sleep architecture by increased catecholamine release due to stimulation of the central nicotinic cholinergic pathways.

Stimulants increase wakefulness and sleep latency and decrease total sleep time. The indirect sympathomimetics reduce REM sleep and increase latency to the first REM sleep period. Most cases of stimulant withdrawal result in REM sleep rebound with hypersomnia.

CNS-stimulating drugs may lead to disruption of sleep and subsequent excessive daytime sleepiness. At high levels of arousal, caffeine in moderate doses may induce overarousal, leading to prolonged wakefulness and impaired sleep. 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 (28). 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 60% greater risk for trouble sleeping/sleep problems as compared to the placebo group (29). A metaanalysis 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 (20). Generally, higher stimulant doses are associated with reduced sleep duration regardless of medication class.

Caffeine does not affect latency to sleep onset or REM sleep until doses of 300 mg are used. At this dosage, caffeine delays later REM sleep periods and reduces total sleep time while increasing awake time after sleep onset. A study has shown that 400 mg of caffeine taken 6 hours before bedtime has important disruptive effects on sleep (11). The relationship between coffee and sleep is not straightforward. Dynamical systems analyses revealed a significant effect of sleep duration on the change in tendency of caffeine use, ie, a shorter sleep duration predicted a stronger tendency to consume caffeine, and this phenomenon was only found in middle-aged adults and not in older adults (17). The results of this study imply that habitual use of caffeine in real life may not coincide with laboratory findings.

Cocaine use has similar effects of reducing REM sleep and increasing latency to REM sleep as seen with amphetamine. 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. In association with increased arousal and sleep disruption following cocaine use, it may influence the risk of relapse to cocaine because behavioral effects of cocaine are highly correlated with inhibition of dopamine transporter (04).

The pathogenesis and pathophysiology of stimulant-dependent sleep disorder is not well established. Tolerance to stimulant effects and rebound hypersomnia appear to be contributing factors.

Preexistent psychiatric illness may also predispose to stimulant-adverse reactions, including stimulant-dependent sleep disorder.

Molecular mechanisms of sensitization, especially dopaminergic-mediated mechanisms, play an important role in the etiology of stimulant-induced changes and relapses in animals and humans. Genetics play a role in individual variability in caffeine consumption and in the direct effects of caffeine. Both pharmacodynamic and pharmacokinetic polymorphisms have been linked to variation in response to caffeine (33). 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 (05). 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 (07). A previously identified polymorphism in the ADORA2A gene was replicated. These findings demonstrate a role for adenosine A2A receptors in the effects of prolonged wakefulness on vigilant attention and the sleep EEG.

A2A receptors as well as dopamine transporters contribute to individual differences in impaired sleep quality induced by caffeine, and both are preferentially expressed in the striatum, indicating that the striatum plays an important role in sleep-wake regulation. The practical implication of individual differences in caffeine sensitivity and A2A receptor genotype should be taken into consideration in clinical trials of drugs targeting adenosine receptors for sleep-wake disorders and neurodegenerative disorders such as Parkinson disease (21).

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 (06). A study in mice was designed to determine if methylphenidate could alter properties of the circadian clock as an explanation of the mechanism of insomnia in patients with attention deficit hyperactivity disorder treated with methylphenidate (03). Methylphenidate altered the electrical firing rate rhythms in the suprachiasmatic nucleus, suggesting that it alters the underlying circadian clock.

Pramipexole, a nonergot dopamine agonist used for the treatment of Parkinson disease, produces motor benefits that are likely due to dopamine D2 stimulation. Insomnia and daytime sleep attacks are frequent side effects of pramipexole. Pramipexole is also used for the treatment of restless legs syndrome and reduces nighttime awakenings due to this condition.

Epidemiology

The incidence and prevalence of stimulant-dependent sleep disorder are not known.

Prevention

Several clinical strategies may help to reduce the development of stimulant-dependent sleep disorder. The goals, risks, side effects, and benefits of treatment in stimulant-dependent sleep disorder should be clearly presented to the affected individuals. Emphasis on good sleep hygiene is important. Setting realistic goals with the treatment may foster reasonable expectations: not expecting perfect control but, rather, emphasizing alertness at the time when it is most important. The physician should consider starting stimulant treatment at the lowest effective dose and titrating to clinical response, but not exceeding the recommended doses. 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.

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

The psychiatric symptoms sometimes seen with stimulant use must be differentiated from preexistent or comorbid primary psychiatric disorders.

Patients with attention-deficit/hyperactivity disorder 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

Thorough 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 of underlying sleep disorders such as sleep apnea or narcolepsy, polysomnographic evaluation followed by Multiple Sleep Latency Test or Maintenance of Wakefulness Test should be performed after at least 2 weeks of documented abstinence from stimulants.

Management

	• 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.

Prevention. Preventive strategies are important first steps in the management of stimulant-dependent sleep disorder. In view of the disruptive effect of caffeine on sleep, it is recommended that substantial caffeine use should be avoided for a minimum of 6 hours prior to bedtime.

Attention deficit hyperactivity disorder (ADHD) in children and adolescents may be related 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 (16).

Treatment. Some pharmacologic agents may be beneficial for the treatment of stimulant-dependent sleep disorder. A metaanalysis 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 2 trials that met the selection criteria, and there was insufficient evidence for the efficacy of cognitive behavioral treatment (15).

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 (25). 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 (10).

Long-term use of CNS stimulant medications is effective in improving 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 (24). 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 (08). 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. 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 (19).

Clonidine, a nonselective alpha-2 adrenergic agonist that was 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 management of sleep initiation latency and night awakening as well as CNS stimulant-induced sleep disorder in ADHD (26).

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 3 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 (22). 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 (09).

Special considerations

Pregnancy

CNS stimulant use should be avoided in pregnancy because of possible adverse effects on the fetus.

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.