INTRODUCTION — Any medication that passes through the blood-brain barrier has the potential to alter the quality and/or architecture of sleep:
●Sleep quality is the degree to which restful sleep is maintained during the night and the individual feels refreshed on waking and throughout the day. Traditional measures of sleep quality include latency until sleep onset, wakefulness after sleep onset, and/or the duration of sleep.
●Sleep architecture is the structure of sleep. It is cyclical, composed of rapid eye movement (REM) and several non-REM sleep stages, and assessed primarily by electroencephalography (EEG) during polysomnography.
Medication-induced changes in sleep quality and/or architecture are not synonymous with a sleep disturbance; in some cases the changes may be therapeutic, while in others they may be benign or not well understood. The effects of medications that target the central nervous system, cardiovascular system, or respiratory system on sleep quality and sleep architecture are reviewed here. The stages and architecture of normal sleep are described separately. (See "Stages and architecture of normal sleep".)
CENTRAL NERVOUS SYSTEM MEDICATIONS — Commonly prescribed medications that act on the central nervous system (CNS) and can affect sleep include benzodiazepines, nonbenzodiazepine receptor agonists, orexin antagonists, antiseizure drugs, antidepressants, analgesics, and CNS stimulants.
Benzodiazepines and nonbenzodiazepine receptor agonists — Benzodiazepines (eg, diazepam, lorazepam, midazolam) and nonbenzodiazepine receptor agonists (eg, zolpidem, zaleplon, eszopiclone) are commonly prescribed sedative-hypnotic medications used to treat insomnia or anxiety. Both types of agents facilitate gamma-aminobutyric acid (GABA)-mediated inhibition of cell firing by binding to a subunit of the GABA receptor complex called the benzodiazepine receptor. The GABA receptor complex is present throughout the brain, including the ventral lateral preoptic area that controls sleep.
●Sleep quality – All benzodiazepines and nonbenzodiazepine receptor agonists improve sleep quality by reducing the time to sleep onset. The longer-acting agents also improve sleep quality by reducing wakefulness after sleep onset and increasing the total sleep time [1].
●Sleep architecture – Benzodiazepines and nonbenzodiazepine receptor agonists reduce the amount of stage N1 sleep (ie, light sleep), which is considered a therapeutic effect. They may also increase spindle activity during stage N2 sleep (and increase N2 percent). Benzodiazepines and the nonbenzodiazepine receptor agonists have differing effects on stage N3 sleep, which are of uncertain clinical significance. Finally, benzodiazepines and nonbenzodiazepine receptor agonists may modestly reduce rapid eye movement (REM) sleep when used at higher than indicated doses [1].
●Patient-important effects – Patients report that their ease of falling asleep is improved, awakenings are reduced, and sleep time is increased. During the day they experience less sleepiness, greater ability to concentrate, and better daytime performance. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine receptor agonists'.)
Discontinuation may be associated with rebound insomnia (ie, difficulty initiating or maintaining sleep that is worse than that experienced prior to the use of the medication), particularly if high doses are used [2].
Orexin receptor antagonists — The neuropeptides orexin A and orexin B (also referred to as hypocretin1 and hypocretin 2) are thought to have a key role in the regulation of sleep and wake states. Orexin cells located in the hypothalamus activate monoaminergic and cholinergic neurons to produce long consolidated periods of wakefulness. In narcolepsy type 1, there is an absence of orexin in the cerebrospinal fluid (CSF). Three dual orexin receptor antagonists, lemborexant, suvorexant, and daridorexant, are approved for the treatment of insomnia.
●Sleep quality – Orexin antagonists improve sleep onset and maintenance of sleep through all eight hours of the night. In patient-report outcomes, sleep quality is improved and insomnia scale scores are improved [3-5].
●Sleep stages – Orexin antagonists increase REM pressure, as evident by reduced REM latency [6]. Other sleep stages are unaffected.
●Rebound withdrawal – After one year of nightly use of suvorexant at doses up to 40 mg, there was no evidence of rebound or withdrawal effects [7].
●Patient-important effects – Patients report more robust effects on sleep maintenance than on sleep initiation. Depending on dose and half-life, impaired next-morning driving performance has been reported. (See "Pharmacotherapy for insomnia in adults", section on 'Dual orexin receptor antagonists'.)
Melatonin and melatonin receptor agonists — Ramelteon is a melatonin receptor agonist that binds to the melatonin 1 and 2 receptors (MT1, MT2), inhibiting the wakefulness-promoting activity of the suprachiasmatic nucleus [8]. It is generally prescribed for the treatment of sleep onset insomnia (ie, difficulty falling asleep). Tasimelteon, also an MT1 and MT2 agonist, has been approved as a chronobiotic for the treatment of circadian rhythm sleep disorder and non-24-hour sleep-wake disorder [9].
Exogenous melatonin binds to all three melatonin receptors and is less potent than ramelteon. It is also considered a better chronobiotic agent than ramelteon, meaning that it is better at phase shifting circadian rhythms, although there are no direct comparisons [8]. As a result, melatonin may be useful in circadian rhythm disorders, such as jet lag due to eastward travel and delayed sleep-wake phase syndrome. (See "Delayed sleep-wake phase disorder" and "Jet lag" and "Pharmacotherapy for insomnia in adults", section on 'Melatonin receptor agonist (ramelteon)'.)
●Sleep quality – Ramelteon and tasimelteon reduce the latency to sleep onset and increase sleep duration, although ramelteon's effects on sleep continuity are inconsistent. Melatonin also appears to reduce latency to sleep onset; however, its effects on sleep maintenance and duration are inconsistent [10].
●Sleep architecture – Ramelteon reduces the amount of stage N1 sleep (ie, light sleep), which is considered a therapeutic effect, but it has no other effects on sleep architecture. Tasimelteon's sleep stage effects have not been reported. Melatonin's effects on sleep architecture are inconsistent [11].
●Patient-important effects – Patients do not consistently experience increased sleep time or improved daytime function, but the ease of falling asleep improves.
Antiseizure drugs — Older antiseizure drugs (eg, phenobarbital, carbamazepine, and phenytoin) inhibit CNS activity, but the mechanisms of inhibition are poorly characterized. Other drugs (eg, gabapentin, tiagabine, and pregabalin) enhance GABA activity through various mechanisms. Levetiracetam, acts through a unique synaptic vesicle binding site. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)
●Sleep quality – Antiseizure drugs such as phenobarbital and phenytoin appear to decrease sleep latency and increase total sleep time [12]. Phenobarbital may also decrease wakefulness after sleep onset. The effects of the newer agents on sleep quality are less certain due to a paucity of data. In separate studies, gabapentin was associated with a trend toward fewer awakenings after sleep onset [13], pregabalin was shown to reduce sleep latency and increase total sleep time [11], and tiagabine had inconsistent effects on wakefulness after sleep onset and total sleep time [14,15]. Levetiracetam may improve sleep quality in healthy adults [16].
●Sleep architecture – The older antiseizure drugs have variable effects on sleep architecture. Carbamazepine appears to increase stage N3 sleep and reduce REM sleep. Phenobarbital decreases REM sleep, while phenytoin increases stage N1 sleep and decreases stage N3 sleep [12]. The newer antiseizure drugs increase stage N3 sleep, while reducing REM sleep [10].
●Patient-important effects – The clinical significance of enhancement of stage N3 sleep is controversial. Whether patients experience improved sleep restoration or daytime function is yet to be determined. Levetiracetam may increase daytime sleepiness at high doses [16].
Patients tend to develop rapid tolerance (ie, within a week) to the sleep-related effects of the older antiseizure drugs, while tolerance to the newer agents is less evident [8].
Antidepressants — Antidepressant medications include the tricyclic agents (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin antagonist reuptake inhibitors (SARIs), and selective serotonin reuptake inhibitors (SSRIs). Most antidepressants affect both sleep quality and sleep architecture [10].
●Sleep quality – Antidepressant agents have a variable effect on sleep quality, as some are sedating while others are stimulating. The tertiary TCAs (eg, doxepin, amitriptyline, and trimipramine) decrease the latency until sleep onset and wakefulness after sleep onset, whereas the secondary TCAs (eg, nortriptyline and desipramine) have little or no effect on either measure [10]. There is a paucity of data regarding the MAOIs (eg, isocarboxazid, phenelzine, and tranylcypromine) but, generally speaking, they appear to increase wakefulness after sleep onset and decrease total sleep time [12]. Studies of the effects of the SARIs (eg, trazodone and nefazodone) on sleep quality are notable for their inconsistency, with about half of studies showing improvements in measures of sleep quality [10]. Finally, the SSRIs (eg, fluoxetine, paroxetine, and sertraline) appear to increase wakefulness after sleep onset and decrease the total sleep time [12].
●Sleep architecture – All antidepressant agents suppress REM sleep, except the SARIs [10,12]. This is characterized by an increased latency to the onset of REM sleep and a reduction in the percentage of REM sleep. This is particularly profound with the MAOIs [12]. Understanding the effects of antidepressant agents on the other sleep stages is complicated by inconsistent data. Many studies suggest that the tertiary TCAs have no effect on stage N3 sleep, although at least one study showed increased stage N3 sleep [10]. Most studies have found that the SARI, trazodone, increased stage 3 sleep, while the other SARI, nefazodone, decreased stage 3 sleep. The SSRIs appear to increase stage 1 sleep.
●Patient-important effects – It is hypothesized that REM suppression is one mechanism for the mood elevating effects of these drugs, since REM suppression occurs with almost all antidepressants. Notable exceptions are bupropion, trazodone, and nefazodone. Thus, this hypothesis is controversial. The clinical significance of stage N3 sleep enhancement is unknown.
Tolerance to the anticholinergic/sedating effects develops relatively rapidly (usually within a week or two), while the REM-suppressing effects persist. A REM sleep rebound and sleep disturbance can be experienced with the abrupt discontinuation of REM sleep-suppressing antidepressants [17].
Lithium increases total sleep time, may increase slow wave sleep, and decreases REM sleep [18].
Analgesics — Analgesic medications include opioids (eg, codeine, morphine), nonsteroidal antiinflammatory drugs (NSAIDs), and antiinflammatory and antipyretic analgesics (eg, aspirin, acetaminophen). Some over-the-counter (OTC) sleeping aids and cold remedies include analgesics, usually acetaminophen combined with an antihistamine. The effects of analgesic medications on sleep quality and sleep architecture have been scarcely studied.
●Sleep quality – The effects of opioids on sleep quality differ among healthy individuals and those with opioid use disorder. In healthy individuals, opioids have no effect on wakefulness after sleep onset or total sleep time [12,19]. By contrast, among individuals who chronically use opioids, opioids increase wakefulness after sleep onset and decrease total sleep time [12,20]. NSAIDs may impair sleep by inhibiting prostaglandin synthesis, which is believed to promote sleep. In one study of healthy individuals, NSAIDs were associated with increased wakefulness after sleep onset, while acetaminophen was not associated with changes in any measure of sleep quality [21].
●Sleep architecture – Opioids decrease stage N3 sleep and, at higher doses, also decrease REM sleep [12]. This was demonstrated by a double-blind cross-over trial of 42 healthy volunteers [19]. Both sustained-release morphine and methadone decreased the percentage of total sleep time spent in stage N3 sleep, compared with placebo. Neither NSAIDs nor acetaminophen have been shown to alter sleep architecture [21].
●Patient-important effects – Patients who receive opioids for pain may not experience sleep disturbance, as seen in patients who chronically use opioids and some healthy volunteer studies. Long-acting opiates increase daytime sleepiness.
Tolerance to these effects develops rapidly, usually within days. Despite the adverse effects that analgesics can have on sleep in healthy individuals, analgesics may improve sleep if pain is causing a sleep disturbance [22].
Central nervous system stimulants — Medications that stimulate the nervous system (eg, amphetamine, dextroamphetamine, methylphenidate, modafinil) have profound effects on both the quality and architecture of sleep [23,24].
●Sleep quality – CNS stimulants increase the latency to sleep onset and increase wakefulness during the sleep period.
●Sleep architecture – CNS stimulants increase stage N1 sleep and reduce both stage N3 and REM sleep.
●Patient-important effects – Patients develop daytime sleepiness due to reduced sleep. On the other hand, stimulants are used to treat excessive daytime sleepiness in narcolepsy and others disorders of excessive sleepiness.
Rapid tolerance develops to these effects on sleep quality and staging. Upon discontinuation of the drug, there may be increased sleepiness and a rebound in REM sleep [25].
Some over-the-counter medications contain ephedrine or pseudoephedrine, which are similar in chemical structure to amphetamine. These agents have not been studied, but they probably also disrupt sleep.
Atomoxetine is a norepinephrine transporter blocker. In one study, it had no effect on nocturnal sleep latency compared with methylphenidate but it did increase REM latency [26].
Caffeine disrupts sleep through its antagonistic effects on adenosine, an important regulator of the homeostatic sleep drive, and also through effects on circadian timing. In a study of healthy individuals, a dose of caffeine equivalent to that in a double espresso led to a 40-minute phase delay in the circadian melatonin rhythm [27].
ATYPICAL ANTIPSYCHOTIC MEDICATIONS — Atypical antipsychotic medications are often used as hypnotics. Whereas the typical antipsychotic medications have only dopaminergic antagonism, the atypical antipsychotic medications have both serotonergic and dopaminergic antagonism.
●Sleep quality – Studies in healthy volunteers and patients with mood disorders or schizophrenia have found that quetiapine, ziprasidone, olanzapine, and clozapine reduce both sleep latency and wake time after sleep onset. Thus, the atypical antipsychotic medications increase sleep time.
●Sleep architecture – Atypical antipsychotic medications generally suppress REM sleep, while increasing amounts of stage N3.
●Patient-important effects – Owing to their long half-lives, daytime sedation may occur in patients receiving atypical antipsychotic medications.
CARDIAC MEDICATIONS — Cardiac medications with an effect on sleep include the beta adrenergic blockers and centrally acting alpha adrenergic agonists.
Beta blockers — Beta blockers can be categorized as lipophilic or hydrophilic. The lipophilic agents include propranolol, metoprolol, and pindolol, while the hydrophilic agents include atenolol and sotalol. Hydrophilic agents do not cross the blood brain barrier readily and, thus, have no sleep effects.
●Sleep quality – Lipophilic beta blockers are associated with an increase in both the number of awakenings and the amount of awake time following sleep onset [28].
●Sleep architecture – Lipophilic and hydrophilic beta blockers both suppress REM sleep [12,28].
●Patient-important effects – Lipophilic beta blockers are associated with daytime sleepiness, insomnia, hallucinations, and nightmares. This effect does not appear to be secondary to their effects on nighttime sleep alone, since daytime sleepiness is observed after daytime drug administration [12].
Alpha adrenergic agonists — Most of the evidence regarding the impact of centrally acting alpha adrenergic receptor agonists on sleep comes from studies of one agent, clonidine.
●Sleep quality – The effects of alpha adrenergic receptor agonists on sleep quality are uncertain due to inconsistent data. A study of hypertensive patients found that clonidine decreased total sleep time, whereas a study in healthy individuals found that clonidine increased total sleep time [29,30]. There are limited data in children with autism spectrum disorder that clonidine may reduce sleep latency and nighttime awakenings [31].
●Sleep architecture – Clonidine increases the number of shifts to stage N1 sleep or wakefulness, and also suppresses REM sleep [32,33].
●Patient-important effects – The alpha adrenergic receptor agonists increase daytime sleepiness. This effect is observed after daytime drug administration and does not appear to be secondary to their effects on nighttime sleep [12].
PULMONARY MEDICATIONS — Pulmonary medications with an effect on sleep include the methylxanthines and glucocorticoids.
Theophylline — Theophylline is a methylxanthine that is used to treat stable obstructive airways disease and, less frequently, is used as a respiratory stimulant. (See "Theophylline use in asthma" and "Management of apnea of prematurity", section on 'Caffeine' and "Management of refractory chronic obstructive pulmonary disease", section on 'Theophylline'.)
●Sleep quality – Theophylline delays sleep onset and increases wakefulness after sleep onset in healthy individuals. In patients with COPD and asthma, however, theophylline may have no deleterious effects on the quality of sleep. It is possible that the therapeutic effects of the drug on breathing improve sleep to such a degree that it offsets the deleterious effects of the medication on sleep [12].
●Sleep architecture – Theophylline increases stage N1 sleep, but no other effects on sleep architecture are observed.
●Patient-important effects – Patients who take theophylline experience improved sleep and improved daytime alertness.
Glucocorticoids — Systemic glucocorticoids are used to treat a variety of pulmonary diseases. They are widely believed to disrupt sleep, but this is based upon patient reports because their effects have not been well studied polysomnographically. The limited evidence that exists suggests that glucocorticoids are associated with suppression of REM sleep and increased awakening after sleep onset [12,34]. Inhaled glucocorticoids do not appear to have the same adverse effects on sleep in most patients.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Insomnia in adults".)
SUMMARY AND RECOMMENDATIONS
●Any medication that passes through the blood-brain barrier has the potential to alter the quality and/or architecture of sleep. Sleep quality is the degree to which restful sleep is maintained during the night and the individual feels refreshed on waking and throughout the day. Sleep architecture is the structure of sleep; it is cyclical and composed of both rapid eye movement (REM) and several non-REM sleep stages. (See 'Introduction' above.)
●Central nervous system medications that affect sleep quality and/or sleep architecture include benzodiazepines, nonbenzodiazepine receptor agonists, antiseizure drugs, antidepressants, analgesics, and stimulants. The benzodiazepines and nonbenzodiazepine receptor agonists and orexin receptor antagonists are associated with improved ease of falling asleep, reduced awakenings, increased sleep time, less daytime sleepiness, better concentration, and better daytime performance. The other central nervous system medications have a variety of effects. (See 'Central nervous system medications' above.)
●Cardiac medications that affect sleep quality and/or sleep architecture include lipophilic beta adrenergic blockers and centrally acting alpha adrenergic agonists. Both are associated with daytime sleepiness, while the lipophilic beta adrenergic blockers are also associated with insomnia, hallucinations, and nightmares. (See 'Cardiac medications' above.)
●Pulmonary medications known to affect sleep quality and/or sleep architecture include theophylline and systemic glucocorticoids. Theophylline is associated with improved sleep and improved daytime alertness, whereas glucocorticoids are associated with increased awakening after sleep onset. (See 'Pulmonary medications' above.)
