Clinical manifestations

Presentation and course

The main potential drug-induced sleep disorders are listed in Table 1. Complex clinical pictures may arise when two or more drug-induced sleep disorders co-occur or a drug-induced sleep disorder occurs in a subject with other preexisting sleep disorders.

Prognosis and complications

The prognosis for recovery from drug-induced sleep disorders is good if the responsible medication is identified and discontinued.

Biological basis

Etiology and pathogenesis

Drug-induced sleep disorders are due to interaction of a drug with one or more of the neurotransmitters or receptors that are involved in sleep and wakefulness.

Multiple interactions may occur between the disease being treated, preexisting sleep disorders, genetic factors, and effects of drugs.

Biological basis of drug-induced sleep disorders is interaction of a drug with one or more of the neurotransmitters or receptors that are involved in sleep and wakefulness. Multiple interactions between the disease being treated, preexisting sleep disorders, genetic factors, and direct or indirect effects of drugs are possible (37). Etiology should be considered according to the type of disturbance.

Vivid dreams and nightmares. Drugs affecting the neurotransmitters norepinephrine, serotonin, and dopamine are associated with patient reports of nightmares, and agents affecting immunological response to infectious disease are likely to induce nightmares in some patients. Opioids are well known to be associated with vivid dreams and nightmares (26). Ketamine, a non-opiate analgesic/anesthetic agent, is used for management of chronic pain, and it occasionally causes vivid dreams or nightmares, which can be prevented by gradual dose titration. Drugs that have been reported to be associated with these phenomena are listed in Table 2.

Table 2. Drugs Associated with Vivid Dreams and Nightmares

Sleepwalking. Sleepwalking (somnambulism) occurs out of deep NREM sleep and represents a disorder of arousal. It is one form of parasomnia. Subjects with epilepsy and those with a past or family history of sleepwalking are more liable to manifest this as an adverse reaction to drugs. A systematic review of the literature identified 29 drugs, primarily in four classes as possible triggers for sleepwalking: (1) benzodiazepine receptor agonists and other gamma aminobutyric acid (GABA) modulators; (2) antidepressants and other serotonergic agents; (3) antipsychotics; and (4) beta-blockers (32). The strongest evidence for medication-induced sleepwalking was for zolpidem and sodium oxybate. A case report of a patient who suffered a fractured leg during sleepwalking and literature review suggest that propranolol, a beta blocker, can trigger somnambulism, especially if it already occurred in the patient’s past medical history (34). The authors recommend listing somnambulism as a potential side effect of propranolol and treating sleepwalking as an absolute contraindication of propranolol.

The FDA, based on its review of the Adverse Event Reporting System database, found 62 cases of serious injuries from complex sleep behaviors such as sleepwalking, sleep-driving, and sleep-using-a-stove after taking eszopiclone, zaleplon, or zolpidem. A review of the medical literature revealed four more cases reported from 1992 to 2018. Deaths occurred in 20 of these 66 cases. The FDA issued the following statement: "As a result, we are requiring a Boxed Warning, our most prominent warning, to be added to the prescribing information and the patient Medication Guides for these medicines. We are also requiring a Contraindication, our strongest warning, to avoid use in patients who have previously experienced an episode of complex sleep behavior with eszopiclone, zaleplon, and zolpidem."

Sleepwalking has been reported in association with the use of the drugs listed in Table 3.

Table 3. Drugs Associated with Sleepwalking

Sleep disordered breathing during sleep. Snoring is known to increase after intake of alcohol or sedative hypnotics in the evening before going to bed. Snoring alone, in the absence of sleep apnea, has not been proven to disrupt sleep or have a serious adverse effect on health. Obstructive sleep apnea, which is a risk factor for cardiovascular diseases and cognitive decline, is a cause for concern. Drugs may produce central sleep apnea, eg, sleep apnea associated with methylenedioxymethamphetamine, a serotonin neurotoxin, suggests that dysfunction of the brain serotonin system may be involved in the pathophysiology (21). Drugs that have been reported to be associated with central or obstructive sleep apnea are listed in Table 4.

Table 4. Drugs Reported to be Associated with Sleep Apnea with Central or Obstructive Sleep Apnea

Opioids have been shown as cause of central sleep apnea, which resolves after discontinuation of the drug (13). The overall prevalence of central sleep apnea in patients taking chronic opioids is 24% (05). Sleep apnea has been reported in patients receiving methadone as opiate replacement therapy, and prescription of benzodiazepine is not recommended in such situations. Polysomnography may unmask adverse pharmacological effects, eg, central sleep apnea due to central depressant effect of high dose baclofen that resolves with reduction of dose (19).

Sedative-hypnotics, anesthetics, and analgesics alter sleep architecture, which likely contributes to abnormal postoperative sleep architecture with exacerbation of obstructive sleep apnea and postoperative complications (23). Main drugs involved in case reports of drug-induced sleep apnea in the French pharmacovigilance database are benzodiazepines, neuroleptics, and opioids (18).

Data concerning the occurrence of obstructive sleep apnea in subjects using prescription opioids are mixed, with some reports indicating high occurrence, whereas others reporting low, nonsignificant occurrence. Interindividual variability, age range, sex of the subjects investigated, and different phenotypes of obstructive sleep apnea may account for the discrepancies between opioid use and obstructive sleep apnea occurrence in the literature (08).

Sleep paralysis. Sleep paralysis is the transient inability to move or speak during the onset of sleep, or on wakening. It may occur as a manifestation of narcolepsy and is often associated with mental disorder, namely depression. Isolated sleep paralysis during awakening from sleep may occur in the absence of other clinical features of narcolepsy. It is more common in users of anxiolytic medications and hypnotics, such as dual orexin receptor antagonists (DORA).

Enuresis. Enuresis (bedwetting) has been associated with several drugs, as shown in Table 5. The enuretic event is a predominantly nonrapid eye movement sleep phenomenon. Enuresis is an underreported adverse drug reaction of antiepileptic drugs for treatment of childhood epilepsy as it is a condition that could cause embarrassment (30).

Table 5. Drugs Reported to be Associated with Enuresis

Sleep bruxism. Drugs reported to be associated with sleep bruxism are listed in Table 6.

Table 6. Drugs Reported to be Associated with Sleep Bruxism

Sleep bruxism has been reported with antidopaminergic agents such as antipsychotic drugs. Studies of the effects of dopamine agonists such as levodopa and of antagonists such as antipsychotics indicate a central role of dopamine in the pathogenesis of drug-induced bruxism and other mechanisms involving different neurotransmitters are emerging (07). For example, antihistaminergic drugs may induce bruxism due to their disinhibiting effect on the serotonergic system.

Sleep bruxism has been reported with use of antidepressants, mostly selective serotonin reuptake inhibitors. In one study, incidence of antidepressant-induced bruxism was 14%, and the prevalence of bruxism was significantly higher in the antidepressant group (24.3%) than in the control group (15.3%) with paroxetine, venlafaxine, and duloxetine as most frequently involved drugs (36).

Patients under stress are prone to develop drug-induced sleep bruxism. Bruxism is also an adverse effect of drug abuse, eg, ecstasy.

Sleep-related eating disorders. There are several case reports of sleep-related eating disorders in association with use of zolpidem, with recovery following discontinuation of the drug. Most of the published cases involve females, but a male on zolpidem was reported to exhibit an unexpected and bizarre eating behavior during somnambulistic state (06). Zolpidem-induced sleep-related eating disorder has been reported in a patient with restless legs syndrome (38). Drug-induced sleep-related eating disorders should be considered when evaluating patients with nocturnal sleep-related eating disorders.

Rapid eye movement sleep behavior disorder. REM sleep behavior disorder may precede by years or occurs within the context of neurodegenerative diseases (namely synucleinopathies), particularly Parkinson disease and Lewy body dementia. Furthermore, it can be drug-induced or occur on drug withdrawal. Antidepressants are among the drugs associated with this disorder.

A retrospective study of idiopathic REM sleep behavior disorder implied direct or indirect correlations with medication use, although causal relationship could not be demonstrated (35). However, REM sleep behavior disorder has been reported to occur in patients with Parkinson disease after start of mirtazapine therapy, and to resolve after discontinuation of the drug. It has been suggested that development of REM sleep behavior disorder with antidepressants can be an early signal of an underlying synucleinopathies (29).

Finally, antidepressants were reported to increase REM sleep muscle tone in patients with and without REM sleep behavior disorder (22).

Restless legs syndrome. A review of the literature shows that prevalence of restless legs syndrome ranges from 3% to 19% in the general population and has several predisposing factors including use of drugs, with evidence of association with antidepressants, antipsychotics, and antiepileptics (27). Some drugs used to treat restless legs syndrome, particularly dopaminergic drugs, may aggravate symptoms (augmentation).

Sleep-related leg cramps. These have been reported as adverse reactions to treatment with diuretics, vincristine, beta2 agonists, sodium oxybate, donepezil, oxcarbazepine, statins, and cholinesterase inhibitors.

Pathomechanism of drug-induced sleep disorder. For drugs to have a disturbing effect on sleep mechanism, access to the tissues of the brain is required. Important factors are lipid solubility of the drug and the ability of the drug to cross the blood-brain barrier. The background disease affecting a person may play a role in the pathomechanism of drug-induced sleep disorder. The occurrence of sleepwalking, sleep-related eating disorder, and rapid eye movement sleep behavior-like disorder among the psychiatric population are likely due to interaction of mental illnesses, sleep disturbances, and psychotropic medications. Sleep-related adverse effects of drugs can be considered according to therapeutic categories, and rebound insomnia is a special entity for the discussion of pathomechanism.

Analgesics. Ketamine, an N-methyl-D-aspartate antagonist, is an effective nonopioid analgesic for headaches and peripheral neuropathic pain. Adverse effects of repeated administration, even at low doses, include increased liver enzymes, nightmares, and hallucinations, as the patients do not develop tolerance against these effects (24).

Antidepressants. Sleep disturbances are generally more prevalent among patients with depression. These disturbances may improve with antidepressant treatment, but there may also be adverse effects due to antidepressant drugs. Some antidepressants adversely affect the physiological structure of sleep, whereas others restore it. Most antidepressants cause REM sleep reduction, generally with increased serotonin function. Intense and prolonged dreams often accompany abrupt withdrawal from antidepressant drugs as a manifestation of REM sleep rebound after drug-induced REM sleep suppression. Investigations suggest patterns of NREM disturbances associated with depression and antidepressants, which may result in a disturbance of the stability of NREM sleep that may predispose to one or more parasomnias (15).

Tricyclic antidepressants promote sleep in patients with insomnia due to depression and are likely to cause drowsiness. Tricyclic antidepressants also disturb REM sleep and are likely to cause nightmares.

Antiparkinsonian drugs. Patients with Parkinson disease treated with dopaminergic agents have frequent abnormal sleep patterns and hallucinations.

Cardiovascular drugs. Lorcainide, an antiarrhythmic agent, is associated with sleep disturbances (difficulty in falling asleep, nightmares, and vivid dreams).

Hypnotic drugs. The FDA has requested all manufacturers of sedative-hypnotic drug products to strengthen their product labeling by including stronger language concerning potential risks. These risks include complex sleep-related behaviors like sleep-driving, defined as driving when not fully awake after ingestion of a sedative-hypnotic product, with no memory of the event. Revised labeling includes the following medications:

Pathomechanism of drug-induced sleep apnea. Several drugs may adversely affect respiration during sleep through direct (depression of central respiratory centers, induction of upper airway muscles hypotonia) and indirect effects (induction of sleep structure alterations or weight gain) and are reported to cause/worsen obstructive as well central sleep apnea. Depression of the hypercapnic and hypoxic ventilatory responses are crucial in the pathogenesis of opioid-induced central sleep apnea and ataxic breathing during sleep. A comprehensive review of pathophysiologic mechanisms underpinning central sleep apnea has been published (12).

Sleep in normal persons predisposes to hypoventilation, but reflex muscular dilatation of the pharynx occurs to prevent narrowing and increase respiratory effort. This reflex is depressed by some drugs, resulting in pharyngeal narrowing, which may induce/worsen obstructive sleep apnea. Benzodiazepines have a depressant effect on upper airway muscles and, given as pre-anesthetics to patients with sleep apnea, can lead to severe airway obstruction even when awake.

The prevalence of sleep apnea among hypertensives is high, and sleep apnea can also lead to daytime hypertension. However, the role of antihypertensive drugs in breathing during sleep has not been studied adequately.

Drugs that produce weight gain or alter sleep structure by increasing light NREM sleep and arousals may indirectly contribute to obstructive sleep apnea, the magnitude of this effect depending on the obstructive sleep apnea endo-phenotype featured by several anatomic and physiologic parameters (eg, sex, age, ethnicity, low or high arousal threshold, effectiveness of airway dilator muscles, craniofacial morphology, overweight degree).

Epidemiology

Parasomnias and movement disorders during sleep are common, but there are no epidemiological studies to determine the percentage of those caused by drugs.

Prevention

Observance of generally accepted methods of sleep hygiene reduces the probability of development of drug-induced sleep disorders.

The important preventive measure is avoidance of the use of drugs known to produce disturbances of sleep. Long-term use of sedative-hypnotic drugs should be avoided. Although most withdrawal reactions have been reported with long-acting benzodiazepines, rebound insomnia occurs with greater frequency and severity with short-acting agents. Benzodiazepine therapy should be stopped as early as possible with tapering after moderate dose, prolonged-use therapy, or both.

CNS depressants should be avoided in infants less than one year of age, as they may cause sudden death in apnea-prone infants.

Differential diagnosis

Confusing conditions

There are no characteristic clinical features of sleep disorders associated with drugs. The diagnosis is based on history of drug use and findings of sleep laboratory examinations to document the disturbances related to drug use. Drug-induced sleep disorders need to be differentiated from the disorders known to occur as a manifestation of diseases being treated with drugs. Discontinuation of the suspected drug with resulting improvement may help in the diagnosis.

Patients with advanced Parkinson disease have sleep disturbances that need to be differentiated from those induced by dopaminergic agents, eg, hallucinations.

Sleep disturbances are often associated with delirium, which is often drug-induced. During sleep, there may be nightmares that might merge into hallucinations.

Diagnostic workup

The first (and most important) step is elucidation of a complete drug history. In drug-induced drowsiness, blood levels of a suspected drug should be accurately measured. For example, in an elderly patient with phenytoin toxicity who presented with drowsiness and gait disturbance, free phenytoin level was calculated to be 27 ng/dL (normal 10 to 20 ng/dL) after taking his albumin level into account, whereas total serum phenytoin level was reported to be normal (09). Phenytoin was discontinued with resolution of symptoms.

A proper assessment of sleep disorders requires an overnight polysomnographic study that is usually done in a sleep laboratory. These studies document changes in sleep stages, number of arousals, sleep-related breathing disorders, and movements during sleep. This is not only important for the evaluation of sleep disorders, but also for investigation of the action of drugs on sleep. Activity monitoring by wrist actigraphs has proven its usefulness as an efficient method to assess the rest-activity cycle in sleep research. This technique is capable of measuring drug-induced changes in nocturnal and diurnal behavior.

Management

Antipsychotic-induced sleep disorders. Drug-induced restless legs syndrome generally resolves when the dose is reduced or the drug is withdrawn. For management of periodic limb movement disorder in sleep in psychotic patients, switching the antipsychotic and additional use of a second line medication, such as an antiepileptic or a benzodiazepine, is recommended (03). Increase in doses above 80 mg/d of lurasidone, an antipsychotic for schizophrenia, does not seem to increase efficacy and may be associated with a dose-related increase in sleepiness (02). To manage this side effect, the dose should be reduced to the usually recommended range between 40 and 80 mg/d.

Drug-associated bruxism. Dose of the suspected offending medication may be lowered or the drug may be discontinued, switching to another in the same therapeutic class. The use of a dopamine agonist such as buspirone may be considered (10).

Special considerations

Anesthesia

Anesthetic agents, like other CNS depressants, decrease neural output to upper airway muscles more than they depress the phrenic nerve activity. It is a common observation that normal persons develop upper airway obstruction during light general anesthesia if proper position of the head and neck is not maintained. Severe central apnea can develop following general anesthesia.

The use of opioids should be avoided in patients with preexisting sleep apnea syndrome, and special care is required during intubation and in the postanesthetic period. They should not be extubated until fully conscious.