Insomnia

Two placebo-controlled trials showed that standard or controlled-release levodopa at bedtime may improve sleeping time [56, 57]. A placebo-controlled trial demonstrated that pergolide worsened sleep efficiency and fragmentation [58]. A small open-label trial showed that nocturnal apomorphine infusion [59] reduced awakenings. Rotigotine, pramipexole and ropinirole prolonged-release formulations improved sleep quality [60, 61]. Two small open-label studies [62, 63] reported improvements in sleep quality but aggravation of sleep fragmentation with cabergoline at bedtime.

Specifically designed studies primarily aimed at evaluating the effect of long-acting dopamine agonists on sleep disorders have been carried out only for rotigotine [64]. This double-blind, placebo-controlled trial showed improvement of PD Sleep Scale domain scores (disturbed sleep, motor symptoms at night and PD symptoms at night) and Non-Motor Symptoms Scale scores. However, no significant change was found in PD Sleep Scale scores in an open-label study of an extended-release tablet formulation of pramipexole [65].

Improved sleep was reported in two class II placebo-controlled studies [66, 67] with melatonin (ranging from 3 to 50mg), without appreciable adverse events. A case series with zolpidem [68], a short-acting hypnotic drug, and quetiapine [69] reported an improvement of insomnia. Low-dose clozapine improved nocturnal akathisia and tremor [70].

An MDS evidence-based review on the treatment of PD nonmotor symptoms reported the results of five randomized controlled trials assessed the efficacy of the controlled-release formulations of levodopa/carbidopa, pergolide, eszopiclone (a γ-aminobutyric acid A receptor agonist approved for short-term treatment of primary insomnia in older adults) and melatonin at bedtime to treat insomnia in PD [71]. The review concluded that there was insufficient evidence on the efficacy of these drugs administered at bedtime for the treatment of insomnia in PD.

Recommendations from the AAN and the EFNS/MDS guidelines can be integrated as follows.

Other clinical trials have been performed. As reported by the National Institutes of Health clinical trials registry (clinicaltrials.gov), the randomized double-blinded study of ramelteon (NCT00462254) for the treatment of sleep disturbances in PD has been terminated recently. Ramelteon is a selective melatonin-1 and melatonin-2 receptor agonist currently approved in the USA and Japan for the treatment of insomnia. Two studies are underway to evaluate the effects of rasagiline on sleep disturbances in PD (open-label NCT01032486 and placebo-controlled NCT01178047).

In addition or alternatively to pharmacotherapy, several nonpharmacological options to treat insomnia should be considered in clinical practice [72]: stimulus control therapy, relaxation training, sleep restriction, paradoxical intention, biofeedback, cognitive behavioral therapy [73] and multicomponent therapy have been recommended by the American Academy of Sleep Medicine as effective therapies for insomnia [74], but for these therapies, no evidence of efficacy in PD exists. Recently, a pilot study [73] compared nonpharmacological treatment (cognitive behavioral therapy with bright-light therapy) with doxepin (10mg at bedtime) to treat insomnia, with randomized, but not blinded, treatment allocation. Doxepin is interesting because it has a high affinity for the H1 receptor, making it a selective H1 antagonist at low doses, and it has been shown to display sedating properties. The study showed a significant benefit of doxepin in both primary outcomes (the Insomnia Severity Index and the Scales for Outcomes in Parkinson’s Disease – night scale) at 6 weeks.

RBD

There are no controlled trials that have specifically addressed the treatment of RBD in PD.

The EFNS/MDS guidelines [54] reported two case series [75, 76] suggesting that clonazepam (0.5–2mg) is efficacious. Clonazepam may lead to sedation, exacerbated obstructive breathing and increased risk of falling. Two open-label studies [77, 78] reported conflicting results with pramipexole for RBD in PD. Most antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and mirtazapine, may worsen RBD [79]. The AAN Practice parameter [53] concludes that data on the treatment of RBD in PD are insufficient and in a clinical practice clonazepam and melatonin are often used to treat RBD in the general population.

Recommendations from the AAN and EFNS/MDS are as follows.

Recently, Kunz and Mahlberg [80] conducted a double-blind, placebo-controlled, crossover trial of melatonin in eight patients with RBD, one of whom had PD. A significant improvement in global scores was reported after 4 weeks of 3mg melatonin daily, with a complete resolution of behaviors in four of the eight patients and no reported adverse events.

A randomized, double-blind, crossover trial of rivastigmine in 10 patients with PD and RBD [22], and without response to melatonin and clonazepam, supported the hypothesis that an impairment of cholinergic pathways has been implicated in the development of RBD [81]. The authors showed that the use of rivastigmine (transdermal patch 4.6mg/24 h) resulted in a significant decrease in bed partner-reported RBD episodes compared with placebo.

The use of ramelteon to treat two Japanese patients with PD and multiple-system atrophy, and RBD [82] was also reported. These patients improved symptomatically and had a decrease in the proportion of REM sleep without atonia at polysomnography.

Nonpharmacological therapy includes safety measures, for example the use of padded bed rails [83] or customized bed alarms that play messages from a familiar person, triggered by patient movement [84], and the removal of potentially dangerous objects from near the bed.

RLS and PLMS

Ropinirole and pramipexole are approved by the US Food and Drug Administration to treat RLS in the general population, but there are no controlled trials in patients with PD and RLS. An open-label study of 15 patients with PD and PLMS [63] who were treated with cabergoline found an increased number of awakenings and stage shifts but a reduction of PLMS. Another study found that levodopa/carbidopa administered at bedtime decreased the frequency of spontaneous movements in bed [56]. When RLS and PD coexist, the RLS symptoms may theoretically be treated with the dopaminergic therapy used for PD, as dopamine agonists are effective for treatment of RLS.

With specific regard to the occurrence of such symptoms in PD patients, however, the AAN Practice parameter [53] report that levodopa/carbidopa probably decreases the frequency of spontaneous nighttime leg movements, and data regarding the use of nonergot dopamine agonists to treat RLS and PLMS specifically in patients with PD are insufficient.

Obstructive sleep apnea

Studies on the treatment of OSA in PD patients are virtually nonexistent [85]. Treatment is typically with continuous positive airway pressure (CPAP) and is effective in reducing the symptoms of sleepiness and improving quality-of-life measures in people with moderate and severe OSA [86].

Clinical experience suggests that individual PD patients may have an improvement in daytime sleepiness when using CPAP [83].

EDS

Two small placebo-controlled trials with modafinil [87–89] and an open-label study with methylphenidate [90] found improvements in EDS in PD patients. Modafinil is an orally administered wake-promoting agent, indicated to improve wakefulness in adults with excessive sleepiness associated with OSA, shift work disorder and narcolepsy.

Recommendations from the AAN and EFNS/MDS-ES are based on the following approach:

Recently, a 6-week randomly controlled trial of caffeine was conducted in PD patients to assess effects upon daytime somnolence, motor severity and other nonmotor features [91]. Patients with PD and daytime somnolence (Epworth Sleepiness Scale [ESS] >10) were given caffeine 100mg twice daily for 3 weeks and then 200mg twice daily for 3 weeks, or matching placebo. On the ESS (primary endpoint), there was no significant improvement with caffeine at either dose; however, somnolence improved significantly with caffeine for the secondary outcome on the Clinical Global Impression of Change.

Other clinical trials have been performed. As reported by the National Institutes of Health clinical trials registry (clinicaltrials.gov), an open-label study (NCT00641186) to evaluate the sodium oxybate for the treatment of excessive daytime sleepiness and nocturnal sleep disturbance in patients with mild to moderate PD has been completed.

Dopaminergic drugs may play a significant role in daytime alertness of PD. Treatment with dopamine agonists, including the ergot agonists pergolide and bromocriptine and the nonergot agonists pramipexole and ropinirole, increases the incidence of EDS in patients with PD [92]. Moreover, there is a strong relationship between the dosages of dopaminergic medications and EDS. A recent study found that higher doses of levodopa (≥1000mg) and use of dopamine agonist (vs nonuse) were both predictors of higher ESS scores indicative of more severe EDS [93], although no differences in sleep latency were identified between the different types of dopamine agonists.

Sleep attacks

There are no studies that have specifically addressed the treatment or prevention of sudden-onset sleep in PD.

Recommendations from the AAN and EFNS/MDS are similar to those proposed for excessive daytime somnolence. Levodopa monotherapy is associated with a low risk of sleep attacks, whereas the combination of levodopa and dopamine agonists increases the risk by two- or threefold [37]. Systematic assessment of sleepiness is mandatory in PD patients, since sleep attacks are associated with increased risk of driving accidents and injuries at work.

Management is based mainly on simplification and reduction of the antiparkinsonian drug regimen when possible.