Table 2.

Supporting evidence for treatment strategies to manage Rapid Eye Movement sleep behaviour disorder in individuals with Parkinson's disease.

Treatment strategies	Recommended strategy/drug dosage	Benefits	Possible side effects	Efficacy and safety	Long-term outcomes
Non-pharmacological therapies
Bedroom safety environment	Removing potentially dangerous objects. Installing bedrails. Placing pillows or other soft items between patient and hard structures Sleeping in separate bed from partner.	Patient and bed partner safety.	−	NA	NA
Promote sleep hygiene	Regular sleep schedule/ pattern Avoid caffeine & alcohol after lunch time. Avoid bright light before bedtime 1–2 hrs. Avoid large meal or exercise before bedtime 2–4 hrs. Quiet, ventilated, and dark bedroom environment Increase daytime outdoor activity. Limit daytime napping. Avoid prolonged bed rest during non-sleeping hours.	Improvement in sleep quality.	−	NA	NA
OSA treatment	CPAP. Sleeping in a lateral position. Use of a mouth guard.	Improvement in sleep quality. Reduction in nocturnal motor behaviors.	Discomfort	NA	NA
Reduce potential aggravating factors [94], [95]	Reduction or discontinuation of SSRIs, SNRIs, tricyclic antidepressants, acetylcholinesterase inhibitors, caffeine, or alcohol.	Reduction in their impact on RBD.	Recurrent or worsening of comorbidities or disorders.	NA	NA
Pharmacological therapies
Clonazepam [96], [97], [98]	0.5–2 mg.	Increase in total sleep time, sleep efficiency, N2, N3, and decreased waking after sleep onset. May be beneficial in reducing phasic EMG activity during REM sleep.	Sedative effective extend to morning or daytime. Falls. Risk of addiction. Worsening OSA. Rebound RBD in abrupt withdrawal.	Clonazepam partially improved subjective evaluation of RBD severity but not objective PSG measurement of RBD severity and atonia index. Residual symptoms were common among RBD patients despite treatment. Improvement of sleep quality, NREM sleep structures, frequency of violent/ aggressive dreams and sleep related injury. Minor adverse events associated with daytime somnolence	Effect on RBD behaviors, sleep quality and sleep structures remained approximately 2.5 years of therapy.
Melatonin [99]	3–12 mg (monotherapy or adjuvant with clonazepam).	Reduction in RBD-related injuries. Improvement in subjective night-time sleep.	Headache. Morning sleepiness. Light-headedness. Fatigue.	No differences in RBD events between treatment and placebo groups during the 8 weeks of treatment intervention. However, sleep-onset latency was improved in treatment group. No report of major AEs	NA
Other alternative potential RBD treatments
Ramelteon [100]	8 mg.	Reduction in RBD events. Improvement in subjective night-time sleep. Improvement in PD motor symptoms.	Daytime somnolence. Nausea. Light-headedness. Delirium. Worsening constipation.	Ramelteon reduced probable REM sleep behaviour disorder symptoms and improved sleep quality in PD patients during 12 weeks of treatment. No report of major AEs	NA
Memantine [101]	20 mg.	Reduction in the nocturnal movements and/or vocalizations in PDD and DLB.	Bradycardia. Nausea.	Memantine reduced probable REM sleep behaviour disorder in patients with DLB and PDD during the 24 weeks of treatment compared to placebo. Memantine is well tolerated in DLB and PDD patients.	NA
Rivastigmine patch [102]	4.6 mg.	Reduction in the mean frequency of RBD episodes recorded by bed partners.	Minor peripheral cholinergic action.	Rivastigmine is more effective than placebo in reducing RBD frequency in PD patients with treatment refractory RBD during the 3-week treatment. Minor AEs include orthostatic hypotension	NA
Rotigotine patch [103]	12.36 ± 4.27 mg/day.	Improvement in subjective severity of RBD symptoms (assessed by RBD-HK) and RBDSS score (based on V-PSG). Increase in total sleep time, decreased PLMS index.		Rotigotine improved RBD symptoms, sleep quality and motor symptoms in PD patients during the 12 weeks treatment. No report of major adverse events	NA
Safinamide [104]	50 mg.	Improvement in subjective severity RBD symptoms assessed by RBD-HK (dream-related movement and falling out of bed). Reduction in PDSS-2, UPDRS part II, III. Increase in total sleep time. Improvement in tonic and phasic submental EMG activities and REM density.	Increased risk of dyskinesia.	Safinamide improved subjective and objective outcomes of RBD and sleep quality in PD patients during the 3 months treatment. No report of major adverse events.	NA
Sodium oxybate [105]	6.55 g., in treatment resistant RBD	Reduction in monthly RBD episodes.	Anorexia. Anxiety. Increased sweating. Brain fog.	Sodium oxybate showed more reduction in number of monthly RBD episodes according to a diary and RBD activity per V-PSG compared to placebo during the 4 weeks treatment. The adverse events were more common in treatment group which resolved with dose adjustment.	NA

CPAP, Continuous Positive Airway Pressure; EMG, Electromyography; N2 & N3, Non-Rapid Eye Movement sleep stage 2,3; NA, not applicable; OSA, Obstructive Sleep Apnea; PDSS-2, Parkinson’s Disease Sleepiness Scale-2; PLMS, Periodic Limb Movement During Sleep; RBD, Rapid Eye Movement (REM) Sleep Behavior Disorder; RBD-HK, Rapid Eye Movement (REM) Sleep Behavior Disorder Questionnaire-Hong Kong; RBDSS, RBD Severity Scale; SSRIs. Selective Serotonin Reuptake Inhibitors; SNRIs, Serotonin Norepinephrine Reuptake Inhibitors; UPDRS: Unified Parkinson’s Disease Rating Scale; V-PSG, video polysomnography.