Pharmacological Treatments of Sleep–Wake Disorders: Update 2023

: Biological, environmental, behavioral, and social factors can inﬂuence sleep and lead to sleep disorders or diseases. Sleep disorders are common, numerous, and heterogeneous in terms of their etiology, pathogenesis, and symptomatology. The management of sleep–wake circadian disorders (SWCDs) includes education on sleep hygiene, behavioral strategies, psychotherapy (cognitive behavioral therapy (CBT), particularly), instrument-based treatments (i


Introduction
There is a growing understanding of the neurobiology and functions of sleep and its effects on human health, including brain and mental health [1].More than 1/3 of the global population reports sleep loss [2,3].Insufficient or irregular sleep and sleep-wake disorders adversely affect human health in several dimensions, with both immediate effects such as sleepiness, impairment at work, or reduced psychosocial well-being as well as increased risk for (i.e.,) dementia, stroke, cardiovascular disorders, and depression [4][5][6].
There is also a high economic burden of sleep disorders.In a European study from 2010, the costs of disorders of the brain were calculated.The burden of sleep disorders was high and comparable with mental and neurological disorders [7], i.e., for narcolepsy, the direct and indirect costs reached €10,000 per patient, annually.Recently, several professional societies have aimed at increasing awareness, education, and research on sleep and moving healthcare policy towards healthy sleep [1,6,8].
The neurobiology of sleep and wakefulness is complex and includes not only wake-or sleep-promoting systems but also homeostatic, circadian, and motivational processes [9,10].The neurobiology of sleep is beyond the scope of this review, and reference is made to the relevant literature.
Biological factors, environmental, behavioral, and social factors all can influence sleep.The individual may influence some of these factors, such as sleep times, sleep duration, or body weight.Shift work, a noisy sleep environment, hunger, or psychomental stress due to occupational overload are examples of factors that often cannot be influenced, however.
Sleep disorders are heterogeneous in their pathogenesis and manifestation.The International Classification of Sleep Disorders, 3rd Edition [11], classifies them into sections: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, sleep-related movement disorders, and other sleep disorders.
The management of sleep-wake circadian disorders (SWCDs) includes behavioral strategies, psychotherapy, instrument-based treatments (i.e., positive airway pressure therapy), and pharmacotherapy, depending on the individual disorder.Often, there is a combined or sequential treatment of the diseases, which includes the different forms of therapy.
Pharmacological treatment may sometimes be avoided if there is greater awareness of the need for longer and good sleep leading to lifestyle and behavioral changes (e.g., stress reduction, weight control).
Many SWCDs need long-term pharmacological treatment.Drugs used act on the different neurochemical systems that generate wakefulness or sleep, respectively.Frequently used drugs and their pharmacological, neurobiological, and clinical effects are shown in Table 1.Some medications are an option for specific constellations (e.g., amitriptyline for chronic pain and insomnia) or individual symptoms (e.g., REM sleep-suppressing medication for nightmares).

Pharmacotherapy of Sleep-Wake Circadian Disorders
For most SWCDs, pharmacological treatment is recommended.In this review, pharmacological treatment refers to approved and not-approved drugs used for the corresponding disorder.Natural or herbal medicines or any other complementary or alternative medicines are not included.We here also refer to drug treatment in adults.Only very little comparative data on the clinical effectiveness of drugs are available, and mostly meta-analyses have been used for comparative evaluation.The treatment of common SWCDs is presented.For the pharmacotherapy of rare SWCDs, specific literature is recommended.

Insomnia
Introduction: Chronic insomnia refers to frequent and persistent complaints of initiating or maintaining sleep, resulting in dissatisfaction and daytime impairment.This definition may vary depending on the nosological system (ICD-10; ICD-11; ICSD-3 [11], or Diagnostic and Statistical Manual of Mental Disorders, DSM-V) used.Insomnia is the most frequent SWCD.Epidemiological data indicate a 9 to 48%, depending on the criteria, frequency of complaints and daytime consequences [13,14].
Management: For chronic insomnia, cognitive behavioral therapy for insomnia (CBT-I) is recommended as first-line treatment.Pharmacological treatment should be offered if CBT-I is not sufficiently effective or not available [15].In daily practice, many physicians prescribe drugs for insomnia as the first option and exclusively, or in parallel to CBT-I.
Pharmacological treatment: See Table 2. Drug treatment of insomnia is purely symptomatic.In addition to drugs, education strategies and CBT-I are often necessary for the successful long-term treatment of insomnia.Some guidelines and recommendations also differentiate between the treatment of "sleep onset" and "sleep maintenance" insomnia.Particular attention has to be paid to potential psychological dependence on benzodiazepines.
Dual orexin receptor antagonists (DORAs) are novel treatments for insomnia.Several clinical trials and meta-analyses [16][17][18][19][20] showed for all DORAs an improvement in total sleep time in a dose-dependent manner and an improvement in sleep maintenance (suvorexant, [17,[19][20][21], and for daridorexant, [18][19][20]).In a phase II trial, using a randomized, double-blind, placebo-controlled, active-reference (here: zolpidem) study design, only daridorexant reduced the number and duration of longer wake bouts throughout the night compared with placebo [22].Two meta-analyses on daridorexant, however, found no beneficial effect on insomnia [16,17].In a recent study on the comparison of the treatment effectiveness between lemborexant and zolpidem, both drugs, but lemborexant more consistently, showed subjective and objective (polysomnographic findings) benefits compared with placebo [23].The place of DORAs in the treatment of insomnia, in particular for long-term treatment, still needs to be confirmed.The positive effects of the Z-drugs on insomnia have been described in different meta-analyses, with Eszopiclone performing particularly well in one analysis.
Special conditions: Particular recommendations for the elderly are indicated also in Table 2. Some data indicate that trazodone is efficacious in the treatment of insomnia and also in patients suffering from dementia [24].The efficacy and safety of DORA treatment for older individuals are not entirely clear [19,[25][26][27].
Future directions: Dual orexin receptor antagonists (DORA) are a new class of pharmacologic drugs for the treatment of insomnia, and further data on long-term efficacy and safety will appear.Additional studies are needed to evaluate the efficacy of combining newly available pharmacologic treatments, such as DORAs, with other drugs or with non-pharmacologic treatments.Slow-wave sleep (SWS) is often decreased in insomnia, particularly in the elderly.New drugs with a particular effect on SWS are needed.
Management: The therapeutic management of SRBDs comprises general advice as to lifestyle, positional therapy, the treatment of comorbid diseases, and treatment with oral devices, positive airway pressure (PAP) devices, surgical interventions, and hypoglossal nerve stimulation.For OSA and other forms of SRBDs, different PAP treatments are often used as first-line therapy.
Pharmacological treatment: There is not yet any primary pharmacological treatment for SRBDs.Some data indicate that oxygen application and/or the use of acetazolamide may be helpful in some particular SRBDs and as an adjunctive treatment.
Special conditions: • Insomnia: Some patients experience improvement in their non-restorative or disturbed sleep quickly after the initiation of therapy (i.e., with PAP).In others, insomnia symptoms are unchanged, and some describe novel difficulties in sleep initiation in particular.The treatment of insomnia in SRBDs follows the general recommendations for the management of insomnia (see Section 2.1).CBT-I also leads to an improvement in insomnia in treated and untreated comorbid sleep apnea patients [40].It needs to be considered that antidepressant and antipsychotic medicines for insomnia may exacerbate sleep apnea [41].Several studies suggest a neutral response on respiration for GABA-A receptor agonists, (benzodiazepines, Z-drugs) and also for trazodone.In a recent study, using the DORA lemborexant, respiratory safety was demonstrated in subjects with moderate-to-severe OSA [42].

•
Excessive daytime sleepiness (EDS)/fatigue: 5-10% of OSA patients, who are under effective PAP treatment, still describe EDS [43].This condition often is called "residual EDS (R-EDS) in OSA".The daytime symptomatology, however, still needs further differentiation (EDS vs. fatigue vs. cognitive disturbances).Further, it remains unclear whether EDS is the consequence of OSA at all [43].In the last decades, modafinil (off-label in the EU) and armodafinil have been used for the treatment of persistent EDS in OSA.Recently, solriamfetol and pitolisant (see also Section 2.3) have been studied and approved for the treatment of R-EDS in OSA.Both have shown to be efficacious in the reduction in EDS in these populations [44][45][46][47].
Future directions: Several new pathways for the pharmacological treatment of OSA are currently being explored.They include, i.e., the selective norepinephrine reuptake inhibitor atomoxetine in combination with the antimuscarinic oxybutynin.A trial of this combination led to a reduction in the AHI of 62% [48].Recently, a trial with the carbonic anhydrase inhibitor sulthiame in 68 patients with moderate-to-severe OSA resulted in a reduction in the AHI of 41% [49].Although these are promising results, the state of medical evidence is, at present, too scarce to make any sound recommendations on a primary pharmacotherapy for OSA.

Central Disorders of Hypersomnolence (CDH)
Introduction: CDH include primary sleep-wake disorders (narcolepsies, hypersomnias) and hypersomnolence due to or associated with other medical, or psychiatric disorders, medication, or substances.Also, insufficient sleep syndrome is part of this section.For the symptoms of excessive daytime sleepiness and for excessive need for sleep (mean sleep duration >9 h), the prevalence in the general population is 5% and 8%, respectively [50,51].For narcolepsy, the prevalence is approx.0.025 [52].
Management: For narcolepsy and idiopathic hypersomnia, management usually includes both behavioral strategies and pharmacotherapy [53].Psychotherapeutic treatment is also necessary for some patients.
Pharmacological treatment: See Table 3A,B [54][55][56][57][58][59][60].Drug treatment is symptomatic and is oriented primarily to the main symptoms of the diseases (excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep for narcolepsy, and excessive daytime sleepiness and hypersomnia for idiopathic hypersomnia) [54].In a double-blind, randomized trial, the efficacy of pitolisant was compared with that of modafinil with regard to excessive daytime sleepiness: the effect was comparable [61].Special conditions: Stimulant medications can be associated with an increase in heart rate or blood pressure.Pre-existing or comorbid disorders, in particular cardiovascular diseases and psychiatric disorders, have to be taken into consideration when starting or changing a drug treatment.This is particularly true for the group of elderly patients [54].
Future directions: Selective orexin receptor agonists are a promising new class of drugs.Recent pilot trials on orexin receptor agonists (TAK-994, TAK-861) indicated a significant improvement in EDS and cataplexy [62].Other histaminergic drugs and drugs also acting on the orexin system (i.e., mazindol) are under development [63].Recently, a novel concept for the pathophysiology of narcolepsy has been presented [64].If confirmed, different treatment pathways may become available.

Circadian Rhythm Sleep-Wake Disorders (CRSWDs)
Introduction: CRSWDs include disorders with alterations in the circadian timing system including delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm disorder, and non-24 h sleep-wake rhythm disorder.The prevalence of these disorders amongst adults ranges from 0.1% to 7% depending on the definitions used [65,66].In jet lag disorder and shift work disorder, external factors cause the individual's circadian rhythm to be out of phase with environmental demands.In industrialized countries, approx.20% of the workforce is employed in jobs with shift work.The prevalence of shift work disorder is estimated to be between 10% and 40% [67,68].
Management: General approaches to treatment include sleep hygiene education, CBT, regular exercise, and planned light exposure.Drug treatment (melatonin) is usually also part of management [69][70][71].
Pharmacological treatment: In the chronotherapy of CRSWDs, melatonin plays the central pharmacotherapeutic role [31,[72][73][74].Different melatoninergic drugs are available: immediate, fast-acting melatonin; extended-release (ER) melatonin forms; and selective melatonin receptor agonists (Ramelteon, Agomelatin, and Tasimelteon).To induce sleep and phase shifts (chronobiotic effects), the use of an immediate form is appropriate.Often, dosages between 0.5 and 5 mg are recommended.Sometimes, combinations of immediaterelease and extended-release melatonin are necessary.For difficulties in maintaining sleep, ER melatonin or melatonin receptor agonists (MRA) are preferable.Stimulants and/or sleep-promoting treatments other than melatonin are not recommended for the long-term treatment of CRSWDs [75].
Special conditions: Melatonin (2 mg) can be used to promote daytime sleep after a night shift in shift workers [75].There is no recommendation for the use of melatonin in dementia [72].
Future directions: In the context of personalized and precision drug therapy, circadian aspects and chronotherapeutic treatments could take on greater importance.
Management: First-line treatment usually refers to non-pharmacological approaches.This includes the avoidance of triggering factors (i.e., sleep deficiency, other sleep disorders, or drugs), reassurance and environmental (bedroom) safety, and, in some conditions, scheduled awakenings and psychological support.As some NREM parasomnias are often benign and transitory, it may be possible to inform the patient to wait and observe first.Drug treatment includes benzodiazepines, antidepressants, melatonin, and others, and is symptomatic only [78][79][80].
Pharmacological treatment: See Table 4. Several aspects should be considered when it comes to starting long-term drug therapy: the frequency of episodes, the risk of injuries, and functional impairment.Potential side effects of drugs, in particular of GABA-A receptor agonist treatments (i.e., clonazepam), should be noted, such as confusion, dizziness, or memory problems.There is also an increased addiction liability.Some other medications that are not described in Table 4 can be used in particular conditions (i.e., rivastigmine in dementia disorders, or sodium oxybate in narcolepsy) for parasomnias.No objective improvement in parasomnias by melatonin receptor agonists could be shown [81,82].Special conditions: Several drug classes or individual drugs (i.e., selegiline) may induce all types of parasomnias.The drugs may either cause "de novo" parasomnias or exacerbate existing ones [83].

Sleep-Related Movement Disorders
Introduction: Sleep-related movement disorders (SRMDs) have a clinically heterogeneous presentation.Mostly, movements are simple, stereotyped, and involuntary.SRMDs are distinguished according to the part(s) of the body affected and the type of motor activity presented.Restless legs syndrome (RLS) and periodic limb movement (PLM) disorder are the most common SRMDs with a (global) prevalence of 1-10% for RLS.Higher rates are found in women and in the elderly [85].The prevalence of PLM in sleep is approx.30% in the general population [86].Other SRMDs include sleep-related leg cramps, bruxism, and sleep-related rhythmic movement disorders.
Management: For RLS, the first treatment steps include education on sleep hygiene, behavioral strategies, and abstinence from caffeine and alcohol, in particular.Drugs that may increase RLS should be avoided [87].Further, in patients with low iron status (for details, please see references), iron replacement therapy is recommended and presents the only disease-modifying strategy available for RLS [88][89][90].In intermittent RLS, pharmacotherapy can be on demand and different from the daily pharmacological treatment that is given in chronic RLS.See Table 5. PLMS as a symptom of RLS or as a single symptom may reflect a risk factor for cardiovascular and cerebrovascular disease.PLMD refers to PLMS accompanied by fragmented sleep, insomnia, or daytime sleepiness [91].
Pharmacological treatment: Iron substitution is the first component of treatment [88,92,93].Symptomatic drug treatment includes dopaminergic medication (levodopa, dopamine agonists), α2δ ligands (gabapentin, pregabalin), and opioids and GABA-A receptor agonists.See Table 5 [94][95][96][97][98][99].In the few available direct comparative studies (pramipexole versus dual-release levodopa, or gabapentin versus ropinirole), similar effects on RLS were observed [100,101].The treatment effects of pregabalin versus pramipexole on sleep disturbance in restless legs syndrome have been also investigated.In this study, the effects of pregabalin on the periodic limb movement arousal index were comparable to pramipexole, but only pregabalin led to an improvement in sleep architecture [102].In RLS, augmentation may occur.It refers to an overall increase in RLS severity and represents the main complication of dopaminergic treatment [89].Therefore, dopaminergic agents should be avoided, or, if necessary to treat RLS, should be given as a low, and long-acting dose.Other more complex secondary options include the combination of drugs, add-ons of opioids, and split dosing [103,104].
Special conditions: In pregnant RLS patients, iron supplementation is recommended.After the first trimester, and only in severe cases of RLS, clonazepam or low-dose oxycodone may be considered [105,106].
Future directions: Current studies on novel pharmacotherapies for RLS include pitolisant and apomorphine.

Conclusions
Several factors contribute to sleep and lead to SWCDs.The treatment of individual sleep disorders is also multifaceted and includes different forms of therapy.However, for the vast majority of diseases, drug treatment is part of the treatment concept, often even a central component.Fortunately, effective drugs are available for most SWCDs.For some of these diseases (i.e., narcolepsy), new and more specific drugs have been developed in recent years, and a comprehensive range of therapies is now available for sufferers.Unfortunately, there are still many other diseases where there are fewer (new) drug treatment options (i.e., RLS), especially for rare SWCDs.Further and greater efforts should be made to obtain more therapy options here as well.

Table 5 .
Pharmacological treatment of RLS (divided into RLS types and first-and second-line drugs).