Evaluation and treatment of insomnia, daytime sleepiness, and other sleep disorders in Parkinson disease

INTRODUCTION — Problems with sleep are among the most common nonmotor symptoms in Parkinson disease (PD). They have important consequences, including reduced quality of life for patients and care partners and exacerbation of other nonmotor and motor symptoms of the disease.

Sleep problems are more complex in patients with PD than in many other adults due to the effects of the disease, medications used to treat it, and other interacting factors such as age and comorbidities. Successful treatment requires systematic evaluation and a nuanced, often multifaceted approach to diagnosis and management.

Evaluation and management of the most common sleep disorders in patients with PD are reviewed here. Other nonmotor symptoms of PD are reviewed elsewhere. (See "Management of nonmotor symptoms in Parkinson disease" and "Cognitive impairment and dementia in Parkinson disease".)

INSOMNIA — Insomnia is extremely common in patients with PD, affecting 80 percent of patients over the course of the disease [1,2].

Clinical features — Patients may have difficulty falling asleep (sleep initiation insomnia), difficulty staying asleep (sleep maintenance insomnia), or a combination of the two [3]. In patients with PD, sleep maintenance insomnia is more common than sleep initiation insomnia [4].

Patients with sleep initiation insomnia often report trouble falling asleep at the desired bedtime and may lie awake in bed for an extended duration attempting sleep. Patients with sleep maintenance insomnia describe difficulty staying asleep, frequent nighttime awakenings, and/or early morning awakening. Sometimes the complaints are nonspecific, including poor sleep quality, unrefreshing sleep, or daytime sleepiness. (See "Evaluation and diagnosis of insomnia in adults", section on 'Clinical features'.)

The distinction between sleep initiation and maintenance insomnia is not formally recognized in the diagnostic criteria (table 1) [5] but is important in considering contributing factors and treatment strategies.

Contributing factors — Many factors contribute to insomnia in PD. While most are more common in advanced disease, all can be seen in early stages, and the etiology of insomnia may vary over the course of the disease.

●Nocturnal motor symptoms – Tremor, rigidity, and dystonia may contribute to both sleep onset and sleep maintenance insomnia [2,4]. Such symptoms may be manifestations of "wearing off" of symptomatic therapies, resulting in re-emergence of motor symptoms at bedtime or during the night. Bradykinesia and rigidity also contribute to impaired bed mobility, which in turn affects the ability to fall and stay asleep [6].

●Neuropsychiatric symptoms – Depression, anxiety, and panic disorder are common in patients with PD and may contribute to problems falling and staying asleep [7-9]. Anxiety about sleep itself may be a factor as well. In addition, depression may often present with early morning awakening.

Nocturnal psychosis, such as visual hallucinations, can disrupt the sleep of both patients and their bed partners. Nocturnal psychosis can sometimes be difficult to distinguish from dream-related phenomena related to rapid eye movement (REM) sleep behavior disorder (RBD) [10], and neither party may be able to tell whether the patient is asleep or awake. In such cases, psychosis is suggested by the occurrence of symptoms prior to sleep or during periods of awakening during the night.

●Nocturia and other autonomic problems – Urinary frequency during the night is common in PD, especially in males, and is often cited as a reason for sleep maintenance insomnia [4]. Contributing factors include primary urologic problems (eg, benign prostatic hypertrophy) as well as PD-related autonomic dysfunction. (See "Clinical manifestations of Parkinson disease", section on 'Autonomic dysfunction'.)

●Other sleep disorders – Restless leg syndrome (RLS) can contribute to sleep initiation insomnia, and periodic limb movement disorder (PLMD) and obstructive sleep apnea (OSA) can lead to sleep maintenance insomnia. Some patients with RBD report that the dreams and dream enactment episodes contribute to difficulty staying asleep. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Clinical features' and "Rapid eye movement sleep behavior disorder", section on 'Clinical features'.)

●Nocturnal leg cramps and pain – Painful nocturnal cramps, often involving the lower extremities, contribute to insomnia in PD [11]. Other types of pain also affect sleep, including painful sensory symptoms (eg, paresthesias), dystonia, rigidity, and musculoskeletal pain [12]. In some patients, nocturnal pain results from "wearing off" of dopaminergic medications, but in others, pain is present during "on" times as well.

●Medications – Dopaminergic medications themselves can contribute to poor sleep in PD, especially at higher doses, even though they help treat motor symptoms that contribute to insomnia and can have an independent effect on improving sleep quality [2,13]. (See 'Nocturnal motor symptoms' below.)

Among PD medications, selegiline (a monoamine oxidase [MAO] inhibitor), amantadine, and istradefylline (an adenosine antagonist) are particularly likely to affect sleep negatively due to a wake-promoting mechanism of action of the drugs or their metabolites, especially when dosed close to bedtime [2]. By contrast, rasagiline and safinamide (both MAO inhibitors) do not seem to affect sleep adversely and may lead to improvements in subjective or objective sleep in a subset of patients [14,15].

Evaluation — Most patients with PD have at least one cause or contributor to insomnia that can be identified by history, physical examination, and polysomnography (table 2). The goals of the evaluation are to characterize the nature and severity of the sleep problem and identify contributing factors and comorbidities that may be relevant to successful treatment (table 3).

●Symptom inventory – An insomnia questionnaire can be used to structure the history and ascertain symptoms, severity, comorbidities, and potential etiologies. We prefer to use a PD-specific questionnaire such as the Parkinson's Disease Sleep Scale-2 (PDSS-2), which is available for review purposes online but requires licensing for clinical use [16], or the Scales for Outcomes in PD-SLEEP (SCOPA-SLEEP), which can be used for clinical purposes with permission from the Movement Disorders Society [17]. Questionnaires developed for the general population such as the Pittsburgh Sleep Quality Index (PSQI) (table 4 and table 5) [18] and Insomnia Severity Index can also be useful [19].

●Sleep diary – We ask patients to maintain a sleep diary (table 6 and table 7) for five to seven days and collect information on bedtime, time spent in bed, time spent asleep, awakenings, and the relationship of these to PD medication intake and effects, which in turn may help inform whether "wearing off" of PD medications is contributing to insomnia. (See 'Nocturnal motor symptoms' below.)

●Polysomnography – Polysomnography is an important part of the assessment of insomnia in patients with PD and is suggested in all patients (table 8). Its main role is to assess for comorbid primary sleep disorders, including OSA, RBD, and PLMD, which are common reasons for sleep disruption that cannot be diagnosed by history. In-laboratory polysomnography is superior to at-home portable sleep testing for detecting comorbid sleep disorders in PD, but for practical reasons, an in-home portable sleep study may be used as the initial step to assess for OSA. (See "Overview of polysomnography in adults" and "Home sleep apnea testing for obstructive sleep apnea in adults".)

A one-night, in-laboratory polysomnogram in a patient with PD may reveal evidence of abnormalities in sleep architecture, such as reduced slow wave sleep and reduced time spent in REM sleep [20]. Total sleep time and sleep efficiency are both reduced in PD compared with controls. However, objective measures of sleep in PD do not always show a strong relationship with subjective sleep concerns, and a normal polysomnogram does not obviate the need for continued systematic evaluation and treatment of poor sleep.

Differential diagnosis — Insomnia must be distinguished from circadian rhythm disorders such as delayed sleep-wake phase disorder as well as from RLS, as both can present with difficulty initiating sleep at the desired bedtime (table 3). (See "Evaluation and diagnosis of insomnia in adults", section on 'Differential diagnosis'.)

Management — A practical, stepwise approach to treatment of insomnia in patients with PD is presented in the following sections (algorithm 1). The evidence to support many of the treatment approaches is limited, and treatment decisions should be individualized based on patient characteristics and account for risks and adverse effects.

Assess and treat contributing factors — In all patients, we start with systematic assessment and treatment of contributing factors (see 'Contributing factors' above and 'Evaluation' above). When medications are prescribed to address contributors to insomnia, preference should be given to medications that can target more than one contributing factor to minimize polypharmacy and adverse effects.

Medications and other sleep disorders — Prescribed and over-the-counter medications should be carefully reviewed. Medications that may be contributing to insomnia should be stopped, where possible, or dosed earlier in the day to reduce effects on nighttime sleep (table 2). (See "Overview of the treatment of insomnia in adults", section on 'Medication side effects'.)

OSA and other comorbid sleep disorders should be treated in parallel to the treatment of all other contributing factors. (See 'Other sleep disorders' below.)

Nocturnal motor symptoms — For patients with motor symptoms at bedtime or breakthrough motor symptoms overnight, PD medication adjustments are the first step in treatment of insomnia. The duration of effect of carbidopa-levodopa and other dopaminergic medications varies from person to person and decreases over the disease course. Thus, a bedtime dose of a PD medication or overnight dosing becomes necessary in some patients. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Approach to "wearing off"'.)

There are several ways to provide increased or more steady symptomatic therapy overnight in patients with PD. Selection is individualized according to treatment history and patient and clinical preferences. In the Movement Disorders Society (MDS) treatment guidelines for nonmotor symptoms of PD, the level of evidence to guide choice of PD medications for sleep problems was considered insufficient for the majority of options, with the exception of rotigotine [21].

●Controlled-release (CR) carbidopa-levodopa – An evening dose of a carbidopa-levodopa CR tablet is useful for nocturnal motor symptoms and may help insomnia secondarily in some patients. In the United States, the carbidopa-levodopa CR formulation is available in 25 mg/100 mg and 50 mg/200 mg tablets. Except in patients whose daytime symptoms are controlled with 100 mg of levodopa per dose, the higher tablet strength of 50 mg/200 mg may be more useful to control nocturnal motor symptoms. Supporting evidence for sleep outcomes is limited, however. In a small placebo-controlled crossover trial in 40 patients with PD and motor fluctuations, a single dose of carbidopa-levodopa CR tablet improved nocturnal motor symptoms but did not have an effect on subjective and objective sleep measures [22].

In some patients, when breakthrough motor symptoms occur during the night despite addition of a CR tablet at bedtime, timed middle-of-the-night dosing of immediate-release levodopa is necessary.

●Long-acting dopamine agonist – Long-acting dopamine agonists may be appropriate in some patients with insomnia with nocturnal motor symptoms [21]. They are of particular utility when comorbid RLS is present. All of the dopamine agonists can exacerbate nocturnal psychosis, and they should be avoided in older patients and in younger patients with risk factors for psychosis (eg, cognitive impairment). Dosing and administration are reviewed separately. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Nonergot dopamine agonists'.)

Sleep has been examined as an outcome in open-label trials or a secondary outcome in randomized trials of long-acting dopamine agonists (rotigotine, extended-release ropinirole, and extended-release pramipexole) for treatment of motor symptoms in PD, and all three agents have shown improvements in subjective sleep symptoms as assessed with questionnaires [23-28]. A meta-analysis of eight randomized controlled trials of rotigotine in PD demonstrated an improvement in the sleep item of nonmotor symptoms scale in PD (mean difference -2.2 points, 95% CI -3.08 to -0.98) but nonsignificant differences on other scales [29].

●On-demand rescue therapies – Use of rapid-acting agents such as sublingual or subcutaneous apomorphine or inhaled levodopa may be considered for insomnia as well, though their use for nocturnal motor symptoms is guided by limited data. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'On-demand rescue strategies'.)

●Device-assisted and surgical therapies – Improved sleep symptoms, including insomnia symptoms, have been shown in randomized trials and open-label studies of all of the device-assisted surgical interventions for advanced PD, including deep brain stimulation [30,31], levodopa intestinal gel [32], and continuous infusion of subcutaneous apomorphine [33,34]. This is likely in large part due to an improvement in nocturnal motor symptoms. The indications for these therapies are primarily motor and are discussed elsewhere. (See "Device-assisted and lesioning procedures for Parkinson disease".)

Neuropsychiatric comorbidities — When insomnia is a prominent symptom of anxiety, depression, panic disorder, or psychosis, treatment of the neuropsychiatric disorder may or may not result in improved sleep. In some cases, insomnia improves along with other symptoms; in others, insomnia needs to be targeted specifically. The overall approach to treating neuropsychiatric comorbidities in patients with PD is reviewed separately. (See "Management of nonmotor symptoms in Parkinson disease".)

Considerations specific to insomnia in patients with PD include the following:

●Where an antidepressant is appropriate, sedating medications such as trazodone [35], mirtazapine, or sertraline, dosed at bedtime, may be useful, although caution is necessary as these medications can exacerbate RLS and RBD. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Safety considerations with SSRI use'.)

●The risks of benzodiazepines in older adults require that these medications are used with great caution, but selective use has a role in some patients with anxiety and insomnia, especially when comorbid RBD is present and has not responded sufficiently to melatonin or when RLS/PLMD requires treatment as well.

●Pimavanserin, a serotonin 5HT2A receptor inverse agonist/antagonist, is approved for treatment of psychosis in patients with PD. Pooled analysis of two randomized trials of pimavanserin for PD-associated psychosis showed that patients with baseline insomnia complaints had an improvement in their nighttime sleep symptoms as measured with the SCOPA-SLEEP questionnaire [36]. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Refractory psychotic symptoms'.)

Nocturia — Nocturia requires evaluation and treatment for primary urologic causes, such as benign prostatic hypertrophy in males. Behavioral modifications, including minimizing intake of fluids close to bedtime and avoiding caffeine, may help in some patients.

When no underlying structural causes can be identified, bladder relaxant therapies (ie, beta-3 adrenergic agonists and antimuscarinics) are the main pharmacologic option (algorithm 2). Vaginal estrogen may be an additional option in some females.

Beta-3 adrenergic agonists (mirabegron, vibegron) have a more favorable adverse event profile in older adults compared with antimuscarinics, and mirabegron has been studied specifically in patients with PD [37,38].

Among antimuscarinic drugs, those with low central nervous system penetration (eg, darifenacin, solifenacin, trospium) are preferred in patients with PD due to lower risk of neurocognitive side effects. All antimuscarinics have peripheral anticholinergic side effects that are important to consider in patients with PD (eg, dry mouth, constipation). The MDS guidelines found insufficient evidence to recommend solifenacin for use for urinary frequency in PD but did list it as possibly useful [21].

Management of nocturia in the general population is discussed in more detail separately. (See "Nocturia: Clinical presentation, evaluation, and management in adults".)

Other nonmotor symptoms — Treating nocturnal pain in PD begins with identifying the etiology, where possible. Some patients experience pain as a "wearing off" phenomenon, and treatment of nocturnal "off" periods is appropriate in these patients, as reviewed above (see 'Nocturnal motor symptoms' above). Rotigotine may be useful in patients with "wearing off"-related nocturnal pain [39,40].

Nocturnal leg cramps are treated as they are in the general population. (See "Nocturnal leg cramps", section on 'Management'.)

For neuropathic-type pain, gabapentinoids (gabapentin, gabapentin enacarbil, pregabalin) may be considered, particularly when comorbid RLS is present [41,42]. (See "Management of restless legs syndrome and periodic limb movement disorder in adults", section on 'Gabapentinoids'.)

Patients with persistent symptoms — For patients with PD who have persistent insomnia despite treatment of contributing factors and those without contributing factors, the approach to insomnia is similar to that in the general population of older adults. Nonpharmacologic therapies are preferred to medication when feasible and effective, and medications are appropriate in selected patients.

Considerations in patients with PD are reviewed here. Treatment guidelines for insomnia in the general population are reviewed in detail separately. (See "Overview of the treatment of insomnia in adults" and "Pharmacotherapy for insomnia in adults" and "Cognitive behavioral therapy for insomnia in adults".)

Nonpharmacologic therapies

●Cognitive behavioral therapy for insomnia (CBT-I) – CBT-I is recommended as first-line therapy for chronic insomnia in older adults [43] and is suggested in patients with PD as well. Access to therapy can be difficult in some regions and for some patients, but virtual and online delivery methods may overcome some of these barriers.

CBT-I is safe, and case series and pilot open-label studies in patients with PD indicate possible benefit [44,45]. In a small trial in which patients were randomly assigned to receive CBT-I (combined with bright light therapy), doxepin, or placebo [46], insomnia symptoms improved with both CBT-I and doxepin, but overall quality-of-life measures did not improve. Components and delivery of CBT-I are reviewed separately. (See "Cognitive behavioral therapy for insomnia in adults".)

●Bright light therapy – Bright light therapy has been explored for daytime sleepiness in patients with PD and may also be useful for insomnia [47-49]. In a small, two-week trial comparing bright light (10,000 lux) with a dim-light control (<300 lux) for one hour twice day in 31 patients with PD, both conditions were associated with improved self-reported nighttime sleep symptoms over baseline [48]. (See 'Bright light therapy' below.)

●Exercise – Exercise interventions have been shown to improve both subjective and objective measures of insomnia in patients with PD. Several forms of exercise have been studied in trials, including resistance training, cardiovascular training, balance-focused training, and physical and occupational therapy in combination with exercise.

A systematic review and meta-analysis of the effect of exercise on sleep in PD identified 12 controlled studies, including 10 randomized trials, in a total of 690 patients with PD [50]. There was variability in study design and sleep assessments, but overall, exercise was found to have a positive effect on subjective sleep quality. On subgroup analysis, interventions involving moderate to maximal intensity exercise has greater effects, and the benefit from mild to moderate intensity interventions was not statistically significant. In the only study that included objective sleep measures via polysomnography, the exercise group showed improved sleep efficiency, increased total sleep time, and reduction in wake after sleep onset, although some subjective sleep measures were better in the control group [51]. Such discordance between objective and subjective sleep measures is not unusual in PD and highlights the importance of considering both outcomes when managing insomnia.

Pharmacotherapy — An overview of medications for insomnia is presented separately. Many of the considerations for older adults apply to patients with PD, including increased risk for side effects and avoidance of benzodiazepines unless other treatments have failed. (See "Pharmacotherapy for insomnia in adults", section on 'Special populations'.)

Options for patients with PD include the following medications:

●Melatonin – Melatonin is suggested as first-line pharmacotherapy for insomnia in most patients with PD, particularly in the presence of comorbid RBD, sleep-onset complaints, or delayed sleep phase. It is generally safe and well tolerated, and several small trials in patients with PD have shown benefit [52-54].

A meta-analysis of seven randomized trials of melatonin in patients with PD demonstrated improvement in subjective sleep quality as assessed by the PSQI and objective sleep as measured by total sleep time on polysomnography, and it was generally safe [54]. Doses in the trials ranged from 2 to 50 mg.

In practice, low doses of melatonin (eg, ≤5 mg) are appropriate for insomnia and delayed sleep phase, as a dose-response effect has not been demonstrated, and doses ≤1 mg may be as effective as higher amounts (see "Pharmacotherapy for insomnia in adults", section on 'Melatonin'). Higher doses may be required for RBD (table 9). (See "Rapid eye movement sleep behavior disorder", section on 'Pharmacotherapy'.)

Ramelteon, a prescription melatonin analogue, is approved for treatment of sleep-onset insomnia in adults and may be useful in patients with PD, although data are limited and cost sometimes limits use. (See "Pharmacotherapy for insomnia in adults", section on 'Ramelteon'.)

●Doxepin – Low doses of doxepin, a tricyclic antidepressant, are approved for treatment of insomnia in adults and may be useful in patients with PD as well. However, careful monitoring is required due to the potential for anticholinergic side effects. In a small trial of 18 patients with PD, doxepin 10 mg improved insomnia symptoms compared with placebo as measured by the Insomnia Severity Index (-9 versus -2 point improvement) and other questionnaires [46]. (See "Pharmacotherapy for insomnia in adults", section on 'Low-dose doxepin'.)

●Others – Use of nonbenzodiazepine benzodiazepine receptor agonists (BZRAs) such as zolpidem and eszopiclone is discouraged in older adults due to risks of oversedation and falls, and they must be prescribed with caution in patients with PD for these reasons as well as for their risk of complex sleep-related behaviors. Experience with zolpidem in patients with PD specifically is very limited.

The MDS task force on treatment of nonmotor symptoms in PD found insufficient evidence for eszopiclone but listed it as possibly useful for insomnia [21]. A small, six-week randomized trial of eszopiclone in 30 patients with PD found that subjective sleep symptoms and nighttime awakenings improved, although total sleep time did not differ compared with placebo [55]. Eszopiclone has the longest half-life of the nonbenzodiazepine BZRAs, and if its use is necessary, it should be used with caution due to increased risk for falls and fractures; the dose should not exceed 2 mg in older adults. (See "Pharmacotherapy for insomnia in adults", section on 'Nonbenzodiazepine BZRAs'.)

We advise patients not to use over-the-counter sleep aids containing diphenhydramine and other antihistamines because patients with PD are at increased risk for anticholinergic side effects as well as exacerbation of RLS. Sedating antidepressants such as trazodone and mirtazapine also carry risks of anticholinergic side effects but may be useful with careful monitoring when comorbid anxiety or depression is present. We do not use benzodiazepines for insomnia unless there are relevant comorbidities (eg, anxiety, RBD) that alter the risk:benefit ratio. (See 'Neuropsychiatric comorbidities' above.)

Other medications that have not been studied in patients with PD or require more data before use can be endorsed include:

●Sodium oxybate – Sodium oxybate (gamma hydroxybutyrate) is a metabolite of gamma-aminobutyric acid (GABA) that is used primarily in the treatment of narcolepsy. Sodium oxybate increases slow wave sleep, and small pilot studies have shown improvements in objective and subjective sleep measures in patients with PD [56,57]. However, it can exacerbate sleep-related breathing disorders and is associated with rapid onset of deep sedation. Therefore, use in patients with PD is not recommended until further safety and efficacy studies have been performed. Use in patients with narcolepsy in the United States requires registration with the Risk Evaluation and Mitigation Strategies (REMS) program. (See "Treatment of narcolepsy in adults", section on 'Oxybates'.)

●Cannabinoids – Preliminary data from small trials indicate that cannabinoids may have efficacy for subjective sleep problems in patients with PD, but more data are needed to better define their role. In a pilot trial of nabilone, a synthetic cannabinoid, in 19 patients with PD, the nabilone group had improved scores on the sleep item of the Unified Parkinson Disease Rating Scale (UPDRS) compared with the placebo group [58]. Adverse effects occurred in most patients but were mild and transient.

●Dual orexin receptor antagonists – Three dual orexin receptor antagonists (daridorexant, lemborexant, and suvorexant) are available in the United States for treatment of insomnia in adults; however, in light of hypothalamic dysfunction and loss of orexin-containing neurons in PD [59,60], they should not be used in patients with PD until safety and efficacy data are available in this population.

OTHER SLEEP DISORDERS

REM sleep behavior disorder in PD — Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia marked by dream enactment behavior and loss of the normal atonia that occurs during REM sleep. It is a highly specific feature of prodromal PD, when it precedes the onset of motor parkinsonism and clinical diagnosis of PD. (See "Rapid eye movement sleep behavior disorder", section on 'Alpha-synuclein neurodegeneration'.)

In those with established PD, RBD is common, occurring in approximately 60 percent of patients. In this patient population, diagnosis and management considerations are similar to those in the idiopathic RBD population. A polysomnography is useful to confirm the diagnosis by demonstrating loss of normal atonia during REM sleep and rule out RBD mimics such as obstructive sleep apnea (OSA) and periodic limb movement disorder (PLMD) [61,62].

Treatment includes institution of safety measures and pharmacotherapy when necessary (algorithm 3). Treatment of comorbid sleep disorders and elimination of exacerbating medications (table 10), such as selective serotonin reuptake inhibitors (SSRIs), is important.

Melatonin and clonazepam are the two first-line therapies for treatment of dream-enactment symptoms in RBD [63]. While there is limited evidence of efficacy for these agents in patients with PD-associated RBD [64-66], studies in patients with PD have been small [54], and in the broader RBD population, melatonin and clonazepam each reduce frequency of dream enactment and increase the duration of REM sleep with atonia [63]. Melatonin is typically preferred for initial therapy based on lower risk of side effects (algorithm 3). Use of clonazepam warrants careful monitoring in patients with PD given the older age and increased risk of falls in this group. (See "Rapid eye movement sleep behavior disorder", section on 'Pharmacotherapy'.)

The effect of dopaminergic medications on RBD symptoms varies. Some patients with RBD experience a reduction in dream-enactment episodes following initiation of levodopa, dopamine agonists, or monoamine oxidase (MAO) inhibitors, while others having an exacerbation [63].

Restless legs syndrome and periodic limb movement disorder — Restless legs syndrome (RLS) and PLMD are sleep-related movement disorders. RLS is common in PD, occurring in approximately 15 percent of PD patients [67]. The diagnostic criteria for RLS (table 11) and PLMD (table 12) are the same in PD as in the general population, but there are a few diagnostic considerations that are unique to PD. Notably, PLMD is highly difficult to diagnose in patients with PD as a diagnosis of PLMD requires both periodic limb movements of sleep (PLMS) and sleep disturbance or daytime dysfunction that cannot be attributed to another factor.

Up to 40 percent of patients with PD have nocturnal leg restlessness, which is distinguished from typical RLS in that the symptoms do not follow the diurnal variation of RLS and are not clearly relieved with movement [68,69]. In addition, leg restlessness is a "wearing off" symptom in some patients [70]; in such cases, strategies for "wearing off" are appropriate for first-line management. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Approach to "wearing off"'.)

Comorbid PLMD appears to be less common in patients with PD compared with the general population, but its diagnosis and management are the same [71,72].

There is limited evidence to guide treatment of RLS and PLMD in patients with PD, but the approach is generally similar to that in the older adult population (algorithm 4). When RLS co-occurs with evening/nocturnal motor symptoms, a long-acting dopamine agonist or levodopa are typically used to target both syndromes. Gabapentinoids (gabapentin, gabapentin enacarbil, pregabalin) are first-line therapies for patients already receiving dopaminergic medications, who are not having "wearing off" effects, and especially when comorbid nocturnal pain is present.

Treatment of RLS is reviewed in more detail separately. (See "Management of restless legs syndrome and periodic limb movement disorder in adults".)

Sleep-related breathing disorders — Underlying brain disease may make patients with PD particularly vulnerable to the consequences of OSA, including excessive daytime sleepiness (EDS) and cognitive dysfunction [73-75].

The presentation, diagnosis, and management of OSA and other sleep-related breathing disorders are largely similar for patients with PD compared with the general population. However, there are a few considerations specific to the PD population.

Restrictive pulmonary disease related to rigidity and bradykinesia has been hypothesized as a risk factor for sleep-related breathing disorders in patients with PD. While rates of OSA are similar to those in the general population, for a given body mass index (BMI), patients with PD may be at higher risk for OSA, perhaps due to these pulmonary factors [76].

Diagnostic sleep testing should be performed in patients with EDS or snoring [77,78]. However, limiting testing to these patients will miss patients with OSA, as studies in patients with PD have found that neither subjective sleepiness nor snoring are predictive of sleep apnea [73,77,79,80].

On polysomnography, patients with PD have less severe desaturations during apneas for a given level of OSA severity (as measured by apnea hypopnea index [AHI]), and they are more likely to have respiratory effort-related arousals (RERAs), which are not detected on home sleep apnea testing (HSAT) [81]. Thus, in a patient for whom there is suspicion for OSA but for whom HSAT is negative, in-laboratory polysomnography should be obtained. (See "Home sleep apnea testing for obstructive sleep apnea in adults", section on 'Limitations'.)

Treatment of OSA can improve mean sleep latency, subjective sleepiness, and other important signs and symptoms, including cognition, in at least a subset of patients with PD [82]. Positive airway pressure therapy is the mainstay of therapy, as discussed in detail separately. (See "Obstructive sleep apnea: Overview of management in adults".)

Circadian rhythm disruption — Patients with PD are at risk for abnormalities in endogenous circadian rhythms resulting from involvement of circadian structures by the neurodegenerative disease process. The amplitude of melatonin secretion may be reduced in individuals with PD taking dopaminergic medications, especially those with daytime sleepiness [83,84].

Circadian rhythm disorders such as advanced sleep phase and delayed sleep phase may be seen in PD and are managed as they are in the general population. (See "Overview of circadian rhythm sleep-wake disorders".)

EXCESSIVE DAYTIME SLEEPINESS — Excessive daytime sleepiness (EDS) is common in PD, occurring in at least one-third of patients, and increases with advancing age and disease duration [85,86].

Evaluation and initial treatment — EDS may present with a range of severity, from subjective sleepiness to irresistible urge to sleep regardless of the situation and circumstances. This can affect quality of life and can be dangerous in situations such as driving.

The etiology of EDS in PD may be multifactorial, although involvement of wake-promoting structures by the neurodegenerative process accounts for at least some of the propensity. Exogenous factors also contribute and are important to identify and modify:

●Reduce dopamine agonists – Dopaminergic medications are an important cause of sleepiness in patients with PD. Dopamine agonists are most likely to cause EDS, but levodopa can as well [2]. Dopamine agonists should be reduced or eliminated as a first-line step, when possible, especially for patients on higher doses.

A variety of other medications can cause EDS, including opioids, antiseizure medications, and certain antihypertensives. (See "Excessive daytime sleepiness due to medical disorders and medications", section on 'Medications'.)

●Treat nocturnal sleep disorders – Subjective and objective measures of nocturnal sleep often do not explain EDS in PD [87]. At least in a subset of patients, however, a nocturnal sleep disorder such as OSA may account for EDS [88,89], and its treatment may improve symptoms. Thus, evaluation and optimization of nocturnal sleep is part of the management approach [11]. (See 'Assess and treat contributing factors' above and 'Other sleep disorders' above.)

●Psychiatric and medical comorbidities – EDS is a manifestation of depression in some patients. Medical comorbidities are important to consider as well, such as chronic lung disease and chronic pain, which frequently disrupt sleep. (See "Excessive daytime sleepiness due to medical disorders and medications", section on 'Medical conditions'.)

●Patient education and safety – EDS raises important considerations related to driving safety and other activities. Driving cessation may be appropriate in certain patients. Prevention and countermeasures related to drowsy driving are reviewed separately. (See "Drowsy driving: Risks, evaluation, and management", section on 'Driver education'.)

Bright light therapy — For patients with persistent EDS despite treatment of contributing factors, we suggest bright light therapy. Exposure to bright light, such as 10,000 lux for 60 minutes per day, improves daytime sleepiness in the general population and appears to be useful in patients with PD as well. In a meta-analysis of five trials in a total of 92 patients with PD and EDS, bright light therapy led to small but significant improvements in daytime function scores [49].

Light boxes are commercially available in various wavelengths and intensities. We generally advise patients to use a broad-spectrum white light box. The recommended distance from the source is dependent on the intensity of emitted light, and instructions for distance are typically provided by the manufacturer (eg, 10,000 lux at 5 feet). The light box should be used every morning for two to four weeks for a sufficient trial. Patients who derive benefit can continue as maintenance therapy.

Exercise — Structured physical activity and exercise also hold promise as a treatment for daytime sleepiness in PD, but evidence to guide specific exercise prescriptions is lacking [90]. In general, patients with PD should be encouraged to meet the recommendations of physical activity for adults. A useful online resource for patients is available from the National Institute on Aging [91]. Exercise likely has benefits similar to those seen in the general adult population and may benefit other aspects specific to PD, including EDS.

Wake-promoting agents — Wake-promoting agents have limited evidence for efficacy in PD but may be tried in select patients who do not respond to other interventions and desire a trial of medication. Options include modafinil [21,92], armodafinil [93], tomoxetine [94], methylphenidate [95], and caffeine [96,97]. It is important to set expectations; any benefit, when present, is usually mild and may not be sustained [21].

Even for modafinil, which is the best studied agent, data are sparse and conflicting [21,92,98-100]. Some studies have suggested that modafinil may lead to subjective improvement in daytime sleepiness in some patients with PD [98,99], though efficacy on objective measures has not been demonstrated. In the largest of these small trials, 40 patients with PD and EDS were randomly assigned to treatment with modafinil in doses of 200 to 400 mg/day or placebo [100]. There was no benefit for modafinil treatment in the primary outcome measure, the ESS (calculator 1), or any of the secondary outcome measures.

Other medications used for sleepiness in patients with narcolepsy are of uncertain benefit in PD. A placebo-controlled crossover trial of solriamfetol, a dopamine-norepinephrine reuptake inhibitor used in patients with narcolepsy, found no major safety concerns but did not find evidence for subjective or objective improvements in sleepiness in 66 patients with PD; additional studies are needed [101].

Sodium oxybate, which enhances slow wave sleep, has been associated with improvements in EDS in an open-label study [57] and in a randomized trial of 12 patients with PD-associated EDS [56]. However, exacerbation of sleep apnea occurred in a subset of patients. Based on the small amount of available data and the safety concerns, additional studies are needed before we would suggest using sodium oxybate in patients with PD.

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: Restless legs syndrome" and "Society guideline links: Parkinson disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Parkinson disease (The Basics)" and "Patient education: Insomnia (The Basics)" and "Patient education: Daytime sleepiness (The Basics)" and "Patient education: Sleep apnea in adults (The Basics)" and "Patient education: What is a sleep study? (The Basics)" and "Patient education: Restless legs syndrome (The Basics)")

●Beyond the Basics topics (see "Patient education: Parkinson disease symptoms and diagnosis (Beyond the Basics)" and "Patient education: Parkinson disease treatment options — medications (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Parkinson disease".)

SUMMARY AND RECOMMENDATIONS

●Insomnia – Insomnia affects at least 80 percent of patients with Parkinson disease (PD) over the course of the disease. Patients may report difficulty falling asleep (sleep-onset insomnia), staying asleep (sleep-maintenance insomnia), or both (table 1); sleep maintenance problems are the most common. (See 'Clinical features' above.)

•Contributing factors – The most common contributing factors in patients with PD are nocturnal motor symptoms ("wearing off"), neuropsychiatric symptoms, nocturia, other sleep disorders, nocturnal leg cramps and pain, and medication side effects. (See 'Contributing factors' above.)

•Evaluation – History and physical examination should characterize the nature and severity of the sleep problem and identify contributing factors and comorbidities that may be relevant to successful treatment (table 3). Polysomnography should be performed to assess for comorbid sleep disorders. (See 'Evaluation' above.)

•Management – Treatment begins with assessment and treatment of contributing factors, including disease-related factors (eg, "wearing off" at bedtime or overnight), comorbid depression and anxiety, nocturia, and other sleep disorders (algorithm 1). (See 'Assess and treat contributing factors' above.)

For persistent insomnia, the approach is similar to that in the general population of older adults. Cognitive behavioral therapy for insomnia (CBT-I) is preferred to medication when feasible and effective, and medications are appropriate in selected patients. (See 'Nonpharmacologic therapies' above.)

Among medications, we suggest melatonin as first-line therapy in most patients with PD (Grade 2C). It is generally safe and well tolerated, and several small trials in patients with PD have shown benefit. Alternatives include low-dose doxepin and, with caution, eszopiclone or zolpidem. We suggest not using duel orexin receptor antagonists due to the potential to exacerbate hypothalamic dysfunction in PD (Grade 2C). (See 'Pharmacotherapy' above.)

●Rapid eye movement (REM) sleep behavior disorder (RBD) – RBD is common in both prodromal PD and fully manifest disease. Treatment involves establishing a safe sleeping environment and use of melatonin or clonazepam to suppress movements (algorithm 3). (See 'REM sleep behavior disorder in PD' above.)

●Restless legs syndrome (RLS) – RLS is common in PD and often disrupts sleep initiation and quality of life (algorithm 4). RLS should be distinguished from leg restlessness that does not follow a diurnal pattern and from symptoms of "wearing off." (See 'Restless legs syndrome and periodic limb movement disorder' above.)

●Sleep-related breathing disorders – Patients with PD may be at higher risk for obstructive sleep apnea (OSA) than the general population when adjusted for body mass index (BMI). Polysomnogram is preferred for diagnostic confirmation of OSA. Home sleep apnea testing (HSAT) may have poor sensitivity for OSA in patients with PD, and a negative study should prompt in-laboratory polysomnography. (See 'Sleep-related breathing disorders' above.)

●Excessive daytime sleepiness (EDS) – Dopamine agonists are an important cause of EDS in patients with PD and should be reduced or discontinued when possible. Other sleep disorders should be assessed and treated. (See 'Evaluation and initial treatment' above.)

For patients with persistent EDS despite treatment of contributing factors, we suggest bright light therapy (Grade 2C). Judicious use of caffeine during the day, or pharmacologic treatment with modafinil or methylphenidate, may offer some benefit when nonpharmacologic options have failed.