Table 3.
Strategies for the management of restless legs syndrome (RLS) and periodic limb movements during sleep in individuals diagnosed with Parkinson's disease: a review of treatment options.
| Treatment strategies | Recommended strategy/drug dosage | Benefits | Possible side effects | Efficacy and safety | Long-term outcomes |
|---|---|---|---|---|---|
| Non-pharmacological therapies | |||||
| Lifestyle interventions | |||||
| Promote regular exercise [120], [121] | Dependent on each patient’s condition (disease severity, economic status, personal acceptance, convenience) for example yoga, walking, or lower body resistance exercise. | Improvement in IRLS scores. Improvement in sleep quality. |
Fatigue. | Active exercise reduced RLS severity score by 39 % compared to lifestyle interventions (cigarette and alcohol cessation, avoidance of excessive caffeine, and proper sleep hygiene) which reduced severity score by 8 % during the 12 weeks study [120]. Yoga group demonstrated significantly greater improvement than controls (Educational Film) in several domains of sleep quality, greater reductions in prevalence of insomnia, and greater increases in average sleep duration during the 8 weeks study [121]. Minor AEs including knee pain and muscle soreness in active exercise group. |
NA |
| Pneumatic compression [122] | Wear the therapeutic device at 40 cmH2O inflated for 5 s per minute for 1 h prior to the onset of symptoms. | Improvement in IRLS scores. Improvement in quality of life, sleepiness (ESS), and fatigue. |
Discomfort. | Therapeutic PCD resulted in greater improvements in the means of all measured variables (IRLS scores, ESS) over the use of sham devices during the 4 weeks treatment. None experienced adverse reactions related to PCD use. |
NA |
| Repetitive transcranial magnetic stimulation (rTMS) [123], [124] | 5 Hz applied to the supplementary motor area: one session every 3 days for a total of 10 sessions [123]. 15-Hz rTMS stimulation of the leg motor representative area of the frontal cortex for 14 days [124] |
Improvement of IRLS scores [123].Improvement of IRLS scores and improvement in sleep quality (PSQI), anxiety (HAM-A) and depression (HAM-D24) [124]. |
Transient headache. Local discomfort at stimulation area. Dizziness. Ipsilateral lacrimation. Generalized seizure (rare). |
Improvement of IRLS scores over sham stimulation after 5th and 10th sessions [123]. rTMS treatment, improve RLS symptoms, anxiety and depression over sham stimulation [124]. |
Ongoing effects up to 2 weeks in most of the patients [123]. Curative effect sustained for 2 months [124] |
| Standard acupuncture [125] | 12 acupoints. | Improvement in sleep quality (movement activity during sleep, during first hour, and ESS). | Pain. Discomfort. |
Standard but not randomly selected acupuncture points reduced abnormal nocturnal leg activity and early sleep activity significantly in week 2, week 4, and week 6 as well as improvement in the IRLS scores and ESS. | NA |
| Vibration pads [126] | Pads applied to calf muscles for 35 min each night and during RLS attacks | Improvement of sleep quality. | Discomfort | Vibrating pad was more effective than sham pad in improving The Medical Outcomes Study Sleep Problems Index II scores during the 4 weeks treatment. However, vibration therapy failed to significantly improve scores on the RLS-QoL or IRLS scales. | NA |
| Movement therapy [127] | Counter strain manipulation: moving the body or limb into a position that reduces tenderness in the point and maintaining that position for ninety seconds. | Improvement of IRLS scores. | Discomfort | Counter strain manipulation for 4 weeks significantly improved IRLS scores over sham therapy, accounting for improvement of 42·2% in the active group compared to 8·7% in the controls. | NA |
| Surgery | |||||
| Deep brain stimulation [128], [129], [130] | STN target. | Improvement in IRLS scores. Reduction in dopaminergic medications. |
General side effects of DBS. Emergence of RLS (rarely). |
Improvement in RLS severity (IRLS scores) [128], [129], sleep quality and quality of life (RLS QoL) [128]. 30–43 % had complete or nearly complete resolution of the symptoms [128], [129]. Activated contacts located in the central sensorimotor region of the STN relieved RLS symptoms while activated contacts in the inferior sensorimotor part of the STN or in the substantia nigra induced RLS symptoms [128]. Improvement of NMSS particularly sleep domain [129]. |
12 months [128], [129] |
| Pharmacological therapies[131] | |||||
| Iron supplementation | |||||
| Ferrous sulfate [132] | Ferrous sulfate 325 mg and vitamin C 100 mg, twice per day. | Maybe beneficial in improvement of RLS symptoms. | Worsening constipation. Nausea. |
Oral ferrous sulfate 325 mg (65 mg elemental iron) and vitamin C 100 mg twice daily for 12 weeks were more effective than placebo for treating RLS (improvement of IRLS score) for patients with serum ferritin 75 µg/l. Ferric carboxymaltose 1000 mg was more effective than placebo for the treatment of moderate to severe RLS in patients with serum ferritin levels < 300 µg/l and transferrin saturation < 45 %. Efficacy was reported at 4 and 6 weeks after treatment. |
Improvement of RLS symptoms up to 30 weeks post treatment for IV iron. |
| Dopamine agonists | |||||
| Pramipexole [133], [134] | 0.25–0.75 mg/day. | Improvement in night-time RLS symptoms. Improvement in overnight motor and non– motor symptoms. Reduction in pain. |
Risk of augmentation. Risk of sleep attack. Other general dopamine agonist adverse effects. |
Pramipexole was more effective than placebo to improve RLS symptoms, sleep quality and QoL during 12––26 weeks of treatment. Pramipexole was well-tolerated with similar withdrawal rate due to AEs compared to placebo. |
NA |
| Ropinirole [135], [136] | 0.78–4.6 mg/day. | Improvement in night-time RLS symptoms. Improvement in overnight motor and non– motor symptoms. |
Risk of augmentation. Other general dopamine agonist adverse effects. |
Ropinirole was more effective than placebo to improve RLS symptoms, sleep quality and QoL during 12––26 weeks of treatment. The AEs reported with ropinirole were consistent with those previously reported with other dopaminergic agonists. |
NA |
| Rotigotine [137], [138] | 2–3 mg/day. | Improvement in night-time RLS symptoms. Improvement in overnight and early-morning motor performance. Reduction in nocturia. |
Risk of augmentation Application site skin reaction. Headache. Other general dopamine agonist adverse effects. |
Rotigotine transdermal patches were more effective than placebo to improve RLS symptoms, sleep quality and QoL. The efficacy was maintained throughout the 6 months period of treatment. The AEs were dose-dependent manner however were lower than reported for other non-ergot oral dopamine agonists despite the longer duration of the rotigotine trial. |
NA |
| Alpha 2 delta ligands | |||||
| Gabapentin [139], [140] | 800 mg/day in divided doses (200 mg/day in patients undergoing hemodialysis) [139]. 600–2,400 mg/day in divided doses [140] |
Improvement in RLS symptoms and reduction in pain [139]. Improvement in IRLS scores, PLMS index, sleep quality (PSQI) and sleep structures (sleep time, sleep efficiency, and slow wave sleep), and reduction in pain [140]. |
Dizziness. Sleepiness. Peripheral edema. |
Gabapentin effectively improved RLS symptoms, sleep outcomes and RLS related pain compared to placebo. The AEs were more common in treatment group however, no significant differences were found in the particular rate of any of these adverse effects [140]. |
NA |
| Gabapentin enacarbil [141], [142] | 1,200 mg, once daily. | Improvement in RLS symptoms. Reduction in pain |
Dizziness. Sleepiness. |
Gabapentin enacarbil significantly improved RLS symptoms, sleep quality, RLS related pain and QoL compared to placebo and was generally well tolerated during 2–12 weeks of treatment [142]. | NA |
| Pregabalin [139] | 150–450 mg/day, 1–3 h before bedtime. |
Improvement in night-time RLS symptoms. Improvement in subjective night-time sleep. Reduction in pain. |
Dizziness. Sleepiness. Two case reports of pregabalin-induced dyskinesia. |
Pregabalin was more effective than placebo for improving RLS symptoms during 6 weeks of treatment, the response was dose-dependent with doses of ≥ 150 mg/day would provide the greatest response to drug. AEs were more common in treatment group, most were mild. |
NA |
| Opioids | |||||
| Oxycodone or prolonged released oxycodone naloxone [143] | 15.9 mg/day (oxycodone) or oxycodone 5–40 mg plus naloxone 2.5–20 mg, twice per day. (efficacious in severe treatment resistant RLS) |
Improvement of leg discomfort, urge to move. Improvement of IRLS scores Improvement in PLMS index, number of awakenings, and sleep efficiency. |
Risk of addiction. Constipation. Fatigue. Sleep-related respiratory problems. Pruritus. Hallucinations. Urinary retention. |
Prolonged release oxycodone–naloxone was effective for improving RLS symptoms, sleep quality and QoL compared to placebo in patients with severe RLS insufficiently treated with first-line drugs. The efficacy sustained through the 40-week extension phase. The AEs were more common in treatment group; however, the tolerability was proportional to those reported in first-line dopaminergic treatments. |
NA |
| Benzodiazepines | |||||
| Clonazepam [144] | 0.5–1.5 mg/day not recommended as first line due to limited well established evidence. |
Unknown benefit but PD patients who use clonazepam have less PLMS and less daytime sleepiness. | Sleepiness. Risk of fall. Risk of addiction. Worsening OSA. |
Subjective improvements of restlessness and dysesthesias Reduction of periodic leg movements in sleep (PMS) index |
NA |
AEs, Adverse events; ESS, Epworth Sleepiness Scale; HAM-A, Hamilton Anxiety Rating Scale; HAM-D24, Hamilton Depression Rating Scale-24; IRLS, International Restless legs Scale; NA, not available; NMSS, Non-Motor Symptoms Scale for Parkinson's Disease; OSA, Obstructive Sleep Apnea; PCD, Pneumatic compression; PLMS, Periodic Limb Movement during Sleep; PSQI, Pittsburgh Sleep Quality Index; QoL, Quality of Life; STN, Subthalamic Nucleus.