Restless Legs Syndrome — Human Clinical Trials
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Trials by Intervention (n = 355)
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Favors treatmentFavors controlMixedNo difference (null)Inconclusive / not assessableResult unknown
149 with 10 or fewer trials:
Trials by Year (n = 345)
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Showing 355 of 355 trials
10.1002/1531-8257(199901)14/1<138//aid-mds1023>3.0.co;2-a
ropinirole
Quasi-Experimental
IRLSSG abbreviated questionnaire score— Mean difference -10.9, p=0.00
Favors treatmentRoB: High
10.1002/1531-8257(200003)15/2<324//aid-mds1020>3.0.co;2-4
amantadine
Quasi-Experimental
RLS rating scale score— Mean difference -3.20, p=0.00
InconclusiveRoB: High
A randomized double‐blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia
Vanessa Short et al.. American Journal of Hematology 99(6) 1077-1083. (2024)
iron
RCTN = 100
Change from baseline in IRLSS score at Week 6
No differenceRoB: Some Concerns
Dissociation of periodic leg movements from arousals in restless legs syndrome
Mauro Manconi et al.. Annals of Neurology 71(6) 834-844. (2012)
pramipexole
RCTN = 46
PLMS index (entire night) - periodic leg movements during sleep per hour
InconclusiveRoB: Some Concerns
A double‐blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome
Arthur S. Walters et al.. Annals of Neurology 24(3) 455-458. (1988)
bromocriptine
CrossoverN = 6
Periodic movements of sleep per hour of sleep— Mean difference -49.0, p=0.03
Favors treatmentRoB: Some Concerns
Effects of Different Exercise Programs on Symptoms, Sleep, and Quality of Life in Patients with Primary Restless Legs Syndrome
Özge Çoban et al.. Movement Disorders Clinical Practice 10(9) 1349-1359. (2023)
aerobic exercise and stretching exercise
RCTN = 24
RLS Symptom Severity— Mean difference 6.33, p=0.02
Favors treatmentRoB: Some Concerns
One‐year treatment with standard and sustained‐release levodopa: Appropriate long‐term treatment of restless legs syndrome?
Claudia Trenkwalder et al.. Movement Disorders 18(10) 1184-1189. (2003)
levodopa/benserazide
Quasi-Experimental
Satisfaction with sleep— Mean difference 3.50, p=0.00
Favors treatmentRoB: High
Treatment of restless legs syndrome with the dopamine agonist alpha‐dihydroergocryptine
Frithjof Tergau et al.. Movement Disorders 16(4) 731-735. (2001)
alpha-dihydroergocryptine
Quasi-Experimental
Overall complaints (daytime) — VAS— Mean difference -18.0, p=0.00
InconclusiveRoB: High
Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome: A double‐blind, placebo‐controlled pilot study
Stiasny-Kolster K. et al.. Movement Disorders 19(12) 1432-1438. (2004)
rotigotine
RCTN = 63
International Restless Legs Syndrome Scale (IRLS) total score— Mean difference 2.50 (-3.50–8.40), p=0.41
No differenceRoB: Some Concerns
Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: A 12‐week, double‐blind, randomized, parallel‐group, placebo‐controlled study
Arthur S. Walters et al.. Movement Disorders 19(12) 1414-1423. (2004)
ropinirole
RCTN = 267
Change from baseline in International Restless Legs Scale (IRLS) score at week 12— Mean difference -2.50 (-4.60–-0.40), p=0.02
Favors treatmentRoB: Low
Validation of the “L‐DOPA test” for diagnosis of restless legs syndrome
Karin Stiasny‐Kolster et al.. Movement Disorders 21(9) 1333-1339. (2006)
levodopa/benserazide
Quasi-Experimental
Severity of symptoms in the legs (L-DOPA test) — change from baseline— Mean difference -52.2
InconclusiveRoB: High
Controlled withdrawal of pramipexole after 6 months of open‐label treatment in patients with restless legs syndrome
Claudia Trenkwalder et al.. Movement Disorders 21(9) 1404-1410. (2006)
pramipexole
RCTN = 150
Time to target event (insufficient therapeutic response)
Favors treatmentRoB: Some Concerns
Ropinirole is effective in the long‐term management of restless legs syndrome: A randomized controlled trial
Jacques Montplaisir et al.. Movement Disorders 21(10) 1627-1635. (2006)
ropinirole
RCTN = 92
Proportion of patients relapsing during double-blind treatment phase— Odds ratio 0.33 (0.13–0.81), p=0.02
Favors treatmentRoB: Some Concerns
Efficacy of pramipexole in restless legs syndrome: A six‐week, multicenter, randomized, double‐blind study (effect‐RLS study)
Wolfgang H. Oertel et al.. Movement Disorders 22(2) 213-219. (2007)
pramipexole
RCTN = 345
International RLS Study Group Rating Scale (IRLS) score— Mean difference -6.60 (-8.60–-4.50), p=0.00
Favors treatmentRoB: Some Concerns
Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: Results from a multi‐center, randomized, active controlled trial
Claudia Trenkwalder et al.. Movement Disorders 22(5) 696-703. (2007)
cabergoline
RCTN = 361
IRLS total score change from baseline to Week 6/8 (short-term primary endpoint)— Mean difference -6.60 (-8.60–-4.70), p=0.00
Favors treatmentRoB: Some Concerns
Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome
Vincenzo Rizzo et al.. Movement Disorders 24(5) 710-715. (2009)
dopaminergic agents
Quasi-Experimental
Motor-evoked potential (MEP) amplitude after paired associative stimulation
InconclusiveRoB: High
A randomized, double‐blind, placebo controlled, multi‐center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome
Ludger Grote et al.. Movement Disorders 24(10) 1445-1452. (2009)
iron
RCTN = 60
International Restless Legs Syndrome Study Group Rating Scale (IRLS) score at week 11— Mean difference -6.30, p=0.02
No differenceRoB: Some Concerns
Rotigotine improves restless legs syndrome: A 6‐month randomized, double‐blind, placebo‐controlled trial in the United States
Wayne A. Hening et al.. Movement Disorders 25(11) 1675-1683. (2010)
rotigotine
RCTN = 505
IRLS sum score— Mean difference -2.20 (-4.50–0.20), p=0.07
No differenceRoB: Some Concerns
Pramipexole versus ropinirole: Polysomnographic acute effects in restless legs syndrome
Mauro Manconi et al.. Movement Disorders 26(5) 892-895. (2011)
pramipexole and ropinirole
Quasi-Experimental
Median survival time
InconclusiveRoB: High
Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome
John W. Winkelman et al.. Movement Disorders 26(11) 2065-2072. (2011)
gabapentin enacarbil
CrossoverN = 136
Wake time during sleep (WTDS)— Mean difference -26.0 (-35.6–-16.4), p=0.00
Favors treatmentRoB: Some Concerns
Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis‐Ekbom Disease): Results from a prospective, multicenter study over 66 weeks
Diego García‐Borreguero et al.. Movement Disorders 27(2) 277-283. (2012)
ropinirole
RCTN = 404
Change from baseline in IRLS total score at week 12 (primary endpoint)— Mean difference -2.10 (-4.00–-0.10), p=0.04
MixedRoB: Some Concerns
Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial
Claudia Trenkwalder et al.. Movement Disorders 32(10) 1478-1482. (2017)
iron
RCTN = 110
International Restless Legs Syndrome Severity Scale (IRLS) total score— Mean difference -2.90 (-5.93–1.02), p=0.16
No differenceRoB: Some Concerns
Increased Blood Pressure Dipping in Restless Legs Syndrome With Rotigotine: A Randomized Trial
Sofiene Chenini et al.. Movement Disorders 35(12) 2164-2173. (2020)
rotigotine
RCTN = 70
Percentage of systolic BP nondippers at end point— Odds ratio 2.92 (1.08–7.89), p=0.03
Favors treatmentRoB: Low
A Randomized, Placebo‐Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome
Diego Garcia‐Borreguero et al.. Movement Disorders 36(10) 2387-2392. (2021)
dipyridamole
CrossoverN = 28
International Restless Legs Rating Scale (IRLS)— Mean difference -8.00, p=0.00
Favors treatmentRoB: Low
Treatment of restless leg syndrome with pergolide—an open clinical trial
Juliane Winkelmann et al.. Movement Disorders 13(3) 566-569. (1998)
pergolide
Quasi-Experimental
RLS symptom severity classification (categorical: no/mild/severe RLS)
InconclusiveRoB: High
Evaluation of periodic leg movements and associated transcranial magnetic stimulation parameters in restless legs syndrome
Yasar Kutukcu et al.. Muscle & Nerve 33(1) 133-137. (2006)
dopaminergic agents
Quasi-Experimental
Cortical Silent Period (CSP) duration - Right Tibialis Anterior— Mean difference -31.2, p=0.01
InconclusiveRoB: High
Carbamazepine in restless legs
Lundvall O. et al.. European Journal of Clinical Pharmacology 25(3) 323-324. (1983)
carbamazepine
CrossoverN = 6
Number of days with sensations of restless legs per week
InconclusiveRoB: High
Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa
Staedt J. et al.. Journal of Neural Transmission 104(4-5) 461-468. (1997)
pergolide
CrossoverN = 11
NMS cluster disturbed time— Mean difference -74.0, p=0.03
Favors treatmentRoB: Some Concerns
Restless legs syndrome is a relevant comorbidity in patients with inflammatory bowel disease
Janek Becker et al.. International Journal of Colorectal Disease 33(7) 955-962. (2018)
iron
Quasi-Experimental
International RLS Severity Scale (IRLS) score — iron supplementation group
InconclusiveRoB: High
Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome
Saletu M. et al.. European Archives of Psychiatry and Clinical Neuroscience 252(4) 185-194. (2002)
pramipexole
CrossoverN = 11
PLM index per hour of sleep (PLM/h TST)— Mean difference -26.8, p=0.03
Favors treatmentRoB: High
Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid
Ilonka Eisensehr et al.. Journal of Neurology 251(5) 579-583. (2004)
levodopa/benserazide
CrossoverN = 20
RLS symptom intensity score— Mean difference -1.70, p=0.02
MixedRoB: Some Concerns
Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study
Birgit Högl et al.. Journal of Neurology 257(2) 230-237. (2010)
levodopa
Quasi-Experimental
Augmentation occurrence (expert consensus diagnosis)
InconclusiveRoB: High
Impairment of sensory-motor integration in patients affected by RLS
Rizzo V. et al.. Journal of Neurology 257(12) 1979-1985. (2010)
dopaminergic agents
Quasi-Experimental
International RLS Rating Scale (IRLS-RS)
Favors treatmentRoB: High
Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS patients: a multicentre, randomized, placebo-controlled study
Benes H. et al.. Journal of Neurology 258(6) 1046-1054. (2011)
ropinirole
RCTN = 266
Montgomery-Asberg Depression Rating Scale (MADRS) total score— Mean difference -3.60 (-5.60–-1.60), p=0.00
Favors treatmentRoB: Some Concerns
Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa and sr-L-dopa in restless legs syndrome
Saletu M. et al.. Journal of Neural Transmission 110(6) 611-626. (2003)
levodopa/benserazide
CrossoverN = 21
PLM index per hour of sleep (PLM/h TST)— Mean difference -15.5, p=0.00
Favors treatmentRoB: Some Concerns
Computerized movement analysis and beta-CIT-SPECT in patients with restless legs syndrome
Mrowka M. et al.. Journal of Neural Transmission 112(5) 693-701. (2005)
levodopa
Crossover
Movement frequency (FREQ) - alternating forearm pronation/supination, hand tapping, finger tapping, hip flexion/extension before and after L-dopa
InconclusiveRoB: High
Lisuride treatment of Restless Legs Syndrome: first studies with monotherapy in de novo patients and in combination with levodopa in advanced disease
Benes H. et al.. Journal of Neural Transmission 113(1) 87-92. (2006)
lisuride
Quasi-Experimental
PLM Index per hour (PLM/h during time in bed)
InconclusiveRoB: High
Comparative placebo-controlled polysomnographic and psychometric studies on the acute effects of gabapentin versus ropinirole in restless legs syndrome
Michael Saletu et al.. Journal of Neural Transmission 117(4) 463-473. (2010)
gabapentin
RCTN = 80
Sleep Efficiency Index— Mean difference 6.90, p=0.01
Favors treatmentRoB: Some Concerns
Postural control in restless legs syndrome with medication intervention using pramipexole
Aulikki Ahlgrén-Rimpiläinen et al.. Neurological Sciences 35(2) 199-204. (2014)
pramipexole
Quasi-Experimental
Center point of force velocity eyes open (CPFV EO)— Mean difference -0.31, p=0.01
No differenceRoB: High
Repetitive transcranial magnetic stimulation in restless legs syndrome: preliminary results
Burcu Altunrende et al.. Neurological Sciences 35(7) 1083-1088. (2014)
repetitive transcranial magnetic stimulation (rtms)
RCTN = 19
International RLS Rating Scale score— Mean difference 2.10, p=0.21
No differenceRoB: High
The effect of vitamin D supplements on the severity of restless legs syndrome
Siraj Wali et al.. Sleep and Breathing 19(2) 579-583. (2015)
vitamin d3
Quasi-Experimental
RLS severity score— Mean difference -16.0, p=0.00
InconclusiveRoB: High
Effects of sleep hygiene training given to pregnant women with restless leg syndrome on their sleep quality
Ayşe Sönmez et al.. Sleep and Breathing 22(2) 527-535. (2018)
sleep hygiene training
Quasi-ExperimentalN = 128
PSQI Total Score— Mean difference -0.39, p=0.35
No differenceRoB: High
Efficacy of vitamin D replacement therapy in restless legs syndrome: a randomized control trial
Wali SO et al.. Sleep and Breathing 23(2) 595-601. (2019)
vitamin d
RCTN = 35
IRLSSG rating scale score (RLS severity score) — all participants— Mean difference 4.20 (-12.8–4.40), p=0.32
No differenceRoB: Some Concerns
Effects of Bariatric Surgery on Sleep Disorder Symptoms and Sleep Quality
Vahit Mutlu et al.. Obesity Surgery 35(12) 5471-5479. (2025)
bariatric surgery
Quasi-Experimental
Restless Legs Syndrome Severity Scale (IRLSSG)— Mean difference -3.04, p=0.00
Favors treatmentRoB: High
10.1007/s12311-012-0382-6
lisuride
Quasi-Experimental
PLMs index (periodic leg movements per hour of sleep)— Mean difference -21.5, p=0.02
InconclusiveRoB: High
Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects
Willi Cawello et al.. Clinical Drug Investigation 34(2) 95-105. (2014)
rotigotine (neupro)
Quasi-Experimental
AUClast of unconjugated rotigotine— Rate ratio 1.10
InconclusiveRoB: High
Sleep and Quality of Life Under Prolonged Release Oxycodone/Naloxone for Severe Restless Legs Syndrome: An Analysis of Secondary Efficacy Variables of a Double-Blind, Randomized, Placebo-Controlled Study with an Open-Label Extension
Wolfgang H. Oertel et al.. CNS Drugs 30(8) 749-760. (2016)
oxycodone/naloxone
RCTN = 304
MOS Sleep Scale - Sleep Disturbance Domain— Mean difference -18.6 (-24.4–-12.9), p=0.00
Favors treatmentRoB: Low
Treatment of Sleep, Motor and Sensory Symptoms with the Orexin Antagonist Suvorexant in Adults with Idiopathic Restless Legs Syndrome: A Randomized Double-Blind Crossover Proof-of-Concept Study
Diego Garcia-Borreguero et al.. CNS Drugs 38(1) 45-54. (2024)
suvorexant
CrossoverN = 41
Wake After Sleep Onset (WASO)— Mean difference -46.5, p=0.00
Favors treatmentRoB: Some Concerns
Acupressure reduces the severity of restless legs syndrome in hemodialysis patients: A cluster-randomized crossover pilot study
Li-Hung Tsai et al.. Biomedical Journal 45(3) 533-541. (2022)
acupressure
CrossoverN = 27
RLS severity (International Restless Legs Syndrome Rating Scale)— Mean difference 3.70 (1.62–5.78), p=0.00
Favors treatmentRoB: High
Effects of Transcutaneous Spinal Direct Current Stimulation in Idiopathic Restless Legs Patients
Heide AC et al.. Brain Stimulation 7(5) 636-642. (2014)
transcutaneous spinal direct current stimulation (tsdcs)
CrossoverN = 20
RLS symptom severity - Visual Analogue Scale— Mean difference -28.8, p=0.00
Favors treatmentRoB: Some Concerns
Relationship of periodic leg movements and severity of restless legs syndrome: A study in unmedicated and medicated patients
Magdolna Hornyak et al.. Clinical Neurophysiology 118(7) 1532-1537. (2007)
pergolide
RCTN = 100
International RLS Study Group Rating Scale (IRLS) total score— Mean difference -10.4
Favors treatmentRoB: Some Concerns
Cutaneous silent period in patients with restless leg syndrome
Jin-Kyu Han et al.. Clinical Neurophysiology 118(8) 1705-1710. (2007)
dopaminergic agents
Quasi-Experimental
Cutaneous Silent Period (CSP) Duration— Mean difference 8.99, p=0.00
Favors treatmentRoB: High
Effect of pramipexole on cutaneous-silent-period parameters in patients with restless legs syndrome
Oğuzhan Öz et al.. Clinical Neurophysiology 123(1) 154-159. (2012)
pramipexole
Quasi-Experimental
Cutaneous silent period latency - upper extremity (UE CSP latency)— Mean difference -0.10, p=0.96
No differenceRoB: High
Evaluation of Gabapentin Enacarbil on Cardiac Repolarization: A Randomized, Double-Blind, Placebo- and Active-Controlled, Crossover Thorough QT/QTc Study in Healthy Adults
Dan Chen et al.. Clinical Therapeutics 34(2) 351-362.e3. (2012)
gabapentin enacarbil
CrossoverN = 54
Time-matched difference in baseline-adjusted QTcIb (ddQTcIb) — gabapentin enacarbil 1200 mg vs placebo— Mean difference -0.30
Favors treatmentRoB: Low
Short-term effects of massage with olive oil on the severity of uremic restless legs syndrome: A double-blind placebo-controlled trial
Morteza Nasiri et al.. Complementary Therapies in Medicine 44 261-268. (2019)
massage with olive oil
RCTN = 60
Total IRLSSG Rating Scale score (RLS severity)— Mean difference -1.55, p=0.36
No differenceRoB: Some Concerns
Thermo-therapy and cryotherapy to decrease the symptoms of restless leg syndrome during the pregnancy: A randomized clinical trial
Hadi Jafarimanesh et al.. Complementary Therapies in Medicine 50 102409. (2020)
cold water immersion
RCTN = 80
Restless Legs Syndrome symptom severity— Mean difference -2.48, p=0.02
Favors treatmentRoB: Some Concerns
Neurocognitive function in patients with idiopathic Restless Legs Syndrome before and after treatment with dopamine-agonist
Andrea Galbiati et al.. International Journal of Psychophysiology 95(3) 304-309. (2015)
pramipexole
Quasi-Experimental
Total Sleep Time (TST)— Mean difference 87.2, p=0.00
Favors treatmentRoB: High
Treatment of Restless Legs Syndrome Improves Agitation and Sleep in Persons with Dementia: A Randomized Trial
Kathy C. Richards et al.. Journal of the American Medical Directors Association 26(5) 105485. (2025)
gabapentin enacarbil
RCTN = 147
Nighttime agitation (5 PM to 7 AM) - CMAI Index— Mean difference -1.67, p=0.00
Favors treatmentRoB: Some Concerns
Evaluation of Acupuncture in the Treatment of Restless Legs Syndrome: A Randomized Controlled Trial
Gholam Reza Raissi et al.. Journal of Acupuncture and Meridian Studies 10(5) 346-350. (2017)
acupuncture plus gabapentin
RCTN = 50
International Restless Legs Syndrome Study Group Rating Scale (IRLSRS)— Mean difference -2.30
Favors treatmentRoB: Some Concerns
Effects of glycerin oil and lavender oil massages on hemodialysis patients’ restless legs syndrome
Neda Mirbagher Ajorpaz et al.. Journal of Bodywork and Movement Therapies 24(1) 88-92. (2020)
lavender oil and glycerin oil massage
RCTN = 105
Restless Legs Syndrome severity score— Mean difference -14.4, p=0.02
Favors treatmentRoB: Some Concerns
Long-term open-label study of pramipexole in patients with primary restless legs syndrome
Yuichi Inoue et al.. Journal of the Neurological Sciences 294(1-2) 62-66. (2010)
pramipexole
Quasi-ExperimentalN = 141
International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score
InconclusiveRoB: High
Whole body and local cryotherapy in restless legs syndrome: A randomized, single-blind, controlled parallel group pilot study
Svenja Happe et al.. Journal of the Neurological Sciences 370 7-12. (2016)
cryotherapy
RCTN = 43
International RLS Severity Scale (IRLS) score— Mean difference -6.10
Favors treatmentRoB: Some Concerns
Feasibility and efficacy of a physical activity intervention for managing restless legs syndrome in multiple sclerosis: Results of a pilot randomized controlled trial
Katie L.J Cederberg et al.. Multiple Sclerosis and Related Disorders 50 102836. (2021)
physical activity intervention
RCTN = 15
Overall RLS Severity (IRLS Total Score)— Mean difference -7.90, p=0.01
Favors treatmentRoB: High
Use of gabapentin for attenuation of symptoms following rapid opiate detoxification (ROD)
Freye E. et al.. Neurophysiologie Clinique/Clinical Neurophysiology 34(2) 81-89. (2004)
gabapentin
Quasi-Experimental
Amplitude of late N100-peak of somatosensory evoked potential (SEP)— Mean difference 3.90, p=0.01
InconclusiveRoB: High
Noninvasive Vagus Nerve Stimulation: A New Therapeutic Approach for Pharmacoresistant Restless Legs Syndrome
Sarah Hartley et al.. Neuromodulation: Technology at the Neural Interface 26(3) 629-637. (2023)
transauricular vagus nerve stimulation (tvns)
Quasi-Experimental
Restless Legs Syndrome severity (IRLS score)— Mean difference -7.30, p=0.00
Favors treatmentRoB: High
Hyperalgesia and functional sensory loss in restless legs syndrome
Karin Stiasny-Kolster et al.. Pain 154(8) 1457-1463. (2013)
levodopa
Quasi-Experimental
IRLS Severity Scale (International RLS Study Group Severity Scale)— Mean difference -5.20, p=0.05
No differenceRoB: High
Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome
Hideto Shinno et al.. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34(3) 522-526. (2010)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLS)— Mean difference -7.20, p=0.00
Favors treatmentRoB: High
Long-term efficacy and safety of gabapentin enacarbil in Japanese restless legs syndrome patients
Yuichi Inoue et al.. Progress in Neuro-Psychopharmacology and Biological Psychiatry 36(2) 251-257. (2012)
gabapentin enacarbil
Quasi-Experimental
International Restless Legs Syndrome Scale (IRLS) total score
InconclusiveRoB: High
Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome
Yuichi Inoue et al.. Progress in Neuro-Psychopharmacology and Biological Psychiatry 40(1) 326-333. (2013)
rotigotine
Quasi-Experimental
IRLSSG Rating Scale (IRLS) total score
InconclusiveRoB: High
Circadian effects of dopaminergic treatment in restless legs syndrome
Diego Garcia-Borreguero et al.. Sleep Medicine 5(4) 413-420. (2004)
levodopa/carbidopa
Quasi-Experimental
Dim Light Melatonin Onset (DLMO)— Mean difference -2.17, p=0.05
No differenceRoB: High
The treatment of restless legs syndrome with intravenous iron dextran
Christopher J. Earley et al.. Sleep Medicine 5(3) 231-235. (2004)
iron
Quasi-Experimental
Global Rating Scale (GRS) score for RLS severity - percent decrease at 2 weeks
InconclusiveRoB: High
Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome
Bliwise DL et al.. Sleep Medicine 6(2) 141-147. (2005)
ropinirole
RCTN = 26
NREM Periodic Leg Movements in Sleep Index (PLMSI)— Mean difference -56.6, p=0.01
Favors treatmentRoB: Some Concerns
Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome
Earley CJ et al.. Sleep Medicine 6(4) 301-305. (2005)
iron
Quasi-Experimental
Global RLS Rating Scale
InconclusiveRoB: High
Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome
Benes H.. Sleep Medicine 7(1) 31-35. (2006)
lisuride
RCTN = 9
International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score— Mean difference -12.9
Favors treatmentRoB: High
Efficacy and safety of pramipexole in idiopathic restless legs syndrome: A polysomnographic dose-finding study—The PRELUDE study
Markku Partinen et al.. Sleep Medicine 7(5) 407-417. (2006)
pramipexole
RCTN = 109
Periodic Limb Movements during Time in Bed Index (PLMI)
Favors treatmentRoB: Some Concerns
Efficacy and tolerability of sumanirole in restless legs syndrome: A phase II, randomized, double-blind, placebo-controlled, dose–response study
Diego Garcia-Borreguero et al.. Sleep Medicine 8(2) 119-127. (2007)
sumanirole
RCTN = 270
IRLS-10 total score change from baseline to end of maintenance— Mean difference -0.14
No differenceRoB: Some Concerns
A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome
Diego Garcia-Borreguero et al.. Sleep Medicine 8(7-8) 742-752. (2007)
ropinirole
Quasi-Experimental
IRLS total score
InconclusiveRoB: High
First night efficacy of pramipexole in restless legs syndrome and periodic leg movements
Mauro Manconi et al.. Sleep Medicine 8(5) 491-497. (2007)
pramipexole
RCTN = 32
PLMS Change Index (normalized change in PLMS index from baseline to treatment night)
Favors treatmentRoB: Some Concerns
Efficacy of rotigotine transdermal system in severe restless legs syndrome: A randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe
Wolfgang H. Oertel et al.. Sleep Medicine 9(3) 228-239. (2008)
rotigotine
RCTN = 341
IRLS total score change from baseline to end of Maintenance Period— Mean difference -1.30 (-5.00–2.30), p=0.23
No differenceRoB: Some Concerns
Clinical efficacy of ropinirole for restless legs syndrome is not affected by age at symptom onset
Richard P. Allen et al.. Sleep Medicine 9(8) 899-902. (2008)
ropinirole
RCTN = 996
Change from baseline in IRLS total score at Week 12 LOCF
Favors treatmentRoB: Some Concerns
Open-label study of the long-term efficacy and safety of pramipexole in patients with Restless Legs Syndrome (extension of the PRELUDE study)
Markku Partinen et al.. Sleep Medicine 9(5) 537-541. (2008)
pramipexole
Quasi-Experimental
International RLS Study Group Rating Scale (IRLS)
InconclusiveRoB: High
One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome
Wolfgang H. Oertel et al.. Sleep Medicine 9(8) 865-873. (2008)
rotigotine
Quasi-Experimental
IRLS total score
InconclusiveRoB: High
A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: Polysomnographic evaluation of periodic leg movements and sleep disturbance
Leni Jama et al.. Sleep Medicine 10(6) 630-636. (2009)
pramipexole
RCTN = 109
Periodic limb movements during time in bed index (PLMI)
Favors treatmentRoB: Some Concerns
Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial
Ferini-Strambi L. et al.. Sleep Medicine 9(8) 874-881. (2008)
pramipexole
RCTN = 369
International RLS Study Group Rating Scale (IRLS) total score— Mean difference -3.80, p=0.00
Favors treatmentRoB: Low
Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study
James Wang et al.. Sleep Medicine 10(9) 973-975. (2009)
iron
RCTN = 18
International Restless Legs Scale (IRLS) score— Mean difference -9.16, p=0.01
Favors treatmentRoB: Some Concerns
Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized, double-blind, placebo-controlled study
Yuichi Inoue et al.. Sleep Medicine 11(1) 11-16. (2010)
pramipexole
RCTN = 41
Periodic Limb Movements in Bed Index (PLMI)
Favors treatmentRoB: Some Concerns
Effects of melatonin and bright light administration on motor and sensory symptoms of RLS
Whittom S. et al.. Sleep Medicine 11(4) 351-355. (2010)
bright light exposure
CrossoverN = 8
SIT-PLM index (Suggested Immobilization Test - Periodic Leg Movements index)— Mean difference 71.0, p=0.04
MixedRoB: High
Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: A randomized, placebo-controlled polysomnographic study
Wolfgang H. Oertel et al.. Sleep Medicine 11(9) 848-856. (2010)
rotigotine
RCTN = 67
Periodic Limb Movement Index (PLMI; PLM/h time in bed)— Rate ratio 4.25 (2.48–7.28), p=0.00
Favors treatmentRoB: Low
A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome
Richard Allen et al.. Sleep Medicine 11(6) 512-519. (2010)
pregabalin
RCTN = 137
IRLS Total Score change from baseline— Mean difference -4.10
Favors treatmentRoB: Some Concerns
Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep
Mauro Manconi et al.. Sleep Medicine 12(1) 47-55. (2011)
pramipexole
RCTN = 23
PLMS index (periodic leg movements during sleep per hour of sleep)— Mean difference -29.9
No differenceRoB: High
Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood
Pasquale Montagna et al.. Sleep Medicine 12(1) 34-40. (2011)
pramipexole
RCTN = 404
IRLS total score change from baseline to week 12— Mean difference 6.10 (4.30–7.90), p=0.00
Favors treatmentRoB: Low
Evaluation of painful sensory symptoms in restless legs syndrome: Experience from two clinical trials
Magdolna Hornyak et al.. Sleep Medicine 12(2) 186-189. (2011)
pramipexole
RCT
RLS-related limb-pain VAS score — Trial 615— Mean difference -12.7, p=0.00
Favors treatmentRoB: Some Concerns
Efficacy and augmentation during 6months of double-blind pramipexole for restless legs syndrome
Birgit Högl et al.. Sleep Medicine 12(4) 351-360. (2011)
pramipexole
RCTN = 331
International RLS Study Group Rating Scale (IRLS) total score — change from baseline— Mean difference -2.60, p=0.01
Favors treatmentRoB: Some Concerns
l-Dopa improves Restless Legs Syndrome and periodic limb movements in sleep but not Attention-Deficit-Hyperactivity Disorder in a double-blind trial in children
Sandra J. England et al.. Sleep Medicine 12(5) 471-477. (2011)
levodopa
FactorialN = 37
Parent Conners' Rating Scale — Oppositional T score
No differenceRoB: Some Concerns
Efficacy and safety of pramipexole in chinese patients with restless legs syndrome: Results from a multi-center, randomized, double-blind, placebo-controlled trial
Jian-Fang Ma et al.. Sleep Medicine 13(1) 58-63. (2012)
pramipexole
RCTN = 306
Change from baseline to week 6 in IRLS total score— Mean difference -4.52, p=0.00
Favors treatmentRoB: Some Concerns
Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: A multi-centred, placebo-controlled preliminary clinical trial
Richard P. Allen et al.. Sleep Medicine 12(9) 906-913. (2011)
iron
RCTN = 46
International Restless Legs Syndrome study group severity scale (IRLS) change from baseline— Mean difference -0.90, p=0.61
No differenceRoB: Some Concerns
Leg movements during wakefulness in restless legs syndrome: Time structure and relationships with periodic leg movements during sleep
Raffaele Ferri et al.. Sleep Medicine 13(5) 529-535. (2012)
pramipexole
RCTN = 35
PLMW index (periodic leg movements during wakefulness per hour)— Mean difference 12.7
No differenceRoB: Some Concerns
Augmentation in the treatment of restless legs syndrome with transdermal rotigotine
Heike Beneš et al.. Sleep Medicine 13(6) 589-597. (2012)
rotigotine
RCTN = 962
Clinically relevant augmentation (MPI criteria)— Risk difference 0.01
Favors treatmentRoB: Some Concerns
Efficacy of vitamins C, E, and their combination for treatment of restless legs syndrome in hemodialysis patients: A randomized, double-blind, placebo-controlled trial
Mohammad Mahdi Sagheb et al.. Sleep Medicine 13(5) 542-545. (2012)
vitamins c and e
RCTN = 60
Absolute change in IRLS sum score from baseline to end of treatment— Mean difference -7.20, p=0.00
Favors treatmentRoB: Some Concerns
A phase II, open-label, non-comparative study of Botulinum toxin in Restless Legs Syndrome
Imad Ghorayeb et al.. Sleep Medicine 13(10) 1313-1316. (2012)
botulinum toxin type a
Quasi-ExperimentalN = 27
Proportion of responders with >=50% improvement of IRLSRS score at week 2
No differenceRoB: High
Lower molecular weight intravenous iron dextran for restless legs syndrome
Yong Won Cho et al.. Sleep Medicine 14(3) 274-277. (2013)
iron
Quasi-Experimental
Korean version of the International RLS Severity Scale (K-IRLS)— Mean difference -6.80, p=0.00
InconclusiveRoB: High
Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study
Yuichi Inoue et al.. Sleep Medicine 14(11) 1085-1091. (2013)
rotigotine
RCTN = 284
International Restless Legs Syndrome Study Group rating scale (IRLS) total score— Mean difference -2.80 (-5.30–-0.30), p=0.03
Favors treatmentRoB: Some Concerns
Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study
Jingyu Zhang et al.. Sleep Medicine 16(1) 181-185. (2015)
pramipexole
RCTN = 204
International RLS Study Group Rating Scale (IRLS) score— Mean difference 3.80, p=0.00
Favors treatmentRoB: Some Concerns
Sternberg working memory performance following treatment with pramipexole in patients with moderate-to-severe restless legs syndrome
Ki-Young Jung et al.. Sleep Medicine 16(6) 703-708. (2015)
pramipexole
Quasi-Experimental
International RLS Severity Scale (IRLS) score— Mean difference -16.1, p=0.00
Favors treatmentRoB: High
Significant association between systolic and diastolic blood pressure elevations and periodic limb movements in patients with idiopathic restless legs syndrome
Werner Cassel et al.. Sleep Medicine 17 109-120. (2016)
rotigotine
RCT
Number of PLM-associated elevations of systolic blood pressure (SBP) during the night
InconclusiveRoB: Some Concerns
Mapping intrinsic functional brain changes and repetitive transcranial magnetic stimulation neuromodulation in idiopathic restless legs syndrome: a resting-state functional magnetic resonance imaging study
Chunyan Liu et al.. Sleep Medicine 16(6) 785-791. (2015)
repetitive transcranial magnetic stimulation (rtms)
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLSSG)— Mean difference -9.00, p=0.00
Favors treatmentRoB: High
Daytime symptoms of restless legs syndrome – clinical characteristics and rotigotine effectiveness
Masayoshi Takahashi et al.. Sleep Medicine 16(7) 871-876. (2015)
rotigotine
RCTN = 284
Change in duration of daytime RLS symptoms (minutes/day)— Mean difference -54.4 (-102–-7.00), p=0.03
Favors treatmentRoB: Some Concerns
Chronic dopaminergic treatment in restless legs syndrome: does it affect the autonomic nervous system?
Camilla Rocchi et al.. Sleep Medicine 16(9) 1071-1076. (2015)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Study Group rating scale (IRLS)— Mean difference -16.8, p=0.00
Favors treatmentRoB: High
Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome
Juliane Schneider et al.. Sleep Medicine 16(11) 1342-1347. (2015)
iron
Quasi-Experimental
International Restless Legs Syndrome Study Group rating scale score (IRLS)— Mean difference -10.0, p=0.01
InconclusiveRoB: High
Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis–Ekbom disease)
Jan-Peer Elshoff et al.. Sleep Medicine 32 48-55. (2017)
rotigotine
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLS)
InconclusiveRoB: High
A method to switch from oral dopamine agonists to rotigotine in patients with restless legs syndrome and mild augmentation
John W. Winkelman et al.. Sleep Medicine 24 18-23. (2016)
rotigotine
Quasi-Experimental
International Restless Legs Syndrome (IRLS) severity score— Mean difference -6.70, p=0.00
Favors treatmentRoB: High
Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome
Yong Won Cho et al.. Sleep Medicine 25 16-23. (2016)
iron
RCTN = 64
International RLS Severity Scale (IRLSS) change from baseline— Mean difference -1.28, p=0.47
No differenceRoB: Some Concerns
Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel
Diego Garcia-Borreguero et al.. Sleep Medicine 34 105-108. (2017)
perampanel
Quasi-Experimental
IRLS (International Restless Legs Syndrome) total score
Favors treatmentRoB: High
Willis-Ekbom disease/restless legs syndrome in patients with opioid withdrawal
Ravi Gupta et al.. Sleep Medicine 45 39-43. (2018)
pregabalin
Quasi-Experimental
Development of RLS during opioid withdrawal (prevalence)
InconclusiveRoB: High
Efficacy of ferric carboxymaltose (FCM) 500 mg dose for the treatment of Restless Legs Syndrome
Yong Won Cho et al.. Sleep Medicine 42 7-12. (2018)
iron
RCTN = 64
International RLS Severity Scale (IRLSS) change from baseline— Mean difference -3.50, p=0.10
No differenceRoB: Some Concerns
Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis
Diego Garcia-Borreguero et al.. Sleep Medicine 45 94-97. (2018)
dipyridamole
Quasi-Experimental
International Restless Legs Syndrome (IRLS) total score— Mean difference -12.7, p=0.01
InconclusiveRoB: High
Impaired short-term plasticity in restless legs syndrome: a pilot rTMS study
Giuseppe Lanza et al.. Sleep Medicine 46 1-4. (2018)
repetitive transcranial magnetic stimulation (rtms)
Quasi-ExperimentalN = 23
Resting Motor Threshold (rMT)
No differenceRoB: High
Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome
John W. Winkelman et al.. Sleep Medicine 48 1-7. (2018)
gabapentin enacarbil
CrossoverN = 131
International Restless Legs Syndrome Rating Scale (IRLS) total score— Mean difference -6.55
Favors treatmentRoB: Some Concerns
Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment
Diego Garcia-Borreguero et al.. Sleep Medicine 55 74-80. (2019)
gabapentin enacarbil
CrossoverN = 39
International Restless Legs Syndrome Scale (IRLS) total score— Mean difference -9.37, p=0.00
Favors treatmentRoB: Some Concerns
Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome
Celia Garcia-Malo et al.. Sleep Medicine 66 123-129. (2020)
iron
Quasi-Experimental
Substantia Nigra Echogenicity Index (SNEI)
InconclusiveRoB: High
Cognitive behavioral therapy for insomnia in restless legs syndrome patients
Mei Ling Song et al.. Sleep Medicine 74 227-234. (2020)
cognitive behavioral therapy for insomnia
RCTN = 40
Insomnia Severity Index (Korean version)— Mean difference -8.40, p=0.00
Favors treatmentRoB: High
Altered cortical gray matter volume and functional connectivity after transcutaneous spinal cord direct current stimulation in idiopathic restless legs syndrome
Li Wang et al.. Sleep Medicine 74 254-261. (2020)
transcutaneous spinal cord direct current stimulation
RCTN = 30
International RLS Rating Scale (IRLS-RS)— Mean difference -8.40
InconclusiveRoB: High
Efficacy and safety of TOMAC for treatment of medication-naïve and medication-refractory restless legs syndrome: A randomized clinical trial and meta-analysis
Haramandeep Singh et al.. Sleep Medicine 122 141-148. (2024)
tonic motor activation (tomac)
RCTN = 45
IRLS total score change from study entry to Week 4 (all participants)— Mean difference -4.42 (-7.26–-1.57), p=0.00
Favors treatmentRoB: Low
Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial
Trenkwalder C. et al.. The Lancet Neurology 7(7) 595-604. (2008)
rotigotine
RCTN = 458
IRLS sum score - change from baseline to end of maintenance— Mean difference -5.10 (-7.60–-2.70), p=0.00
Favors treatmentRoB: Some Concerns
The Treatment of the Restless Legs Syndrome with Clonazepam: A Prospective Controlled Study
Dan Boghen et al.. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 13(3) 245-247. (1986)
clonazepam
CrossoverN = 6
Daily self-rating discomfort score (5-point scale)
No differenceRoB: High
Effectiveness of aripiprazole in treatment of adults with attention deficit disorder and restless legs syndrome
Kikukawa S.. The International Journal of Neuropsychopharmacology 11(03) 439-40. (2008)
aripiprazole
ADD symptoms (organization, planning, procrastination)
InconclusiveRoB: High
In vivo
Mesolimbic D2/3 Receptor Binding Predicts Posttherapeutic Clinical Responses in Restless Legs Syndrome: A Positron Emission Tomography Study
Yumi Oboshi et al.. Journal of Cerebral Blood Flow & Metabolism 32(4) 654-662. (2012)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLSS) score
InconclusiveRoB: High
Incidence of periodic leg movements and of the restless legs syndrome during sleep following acute physical activity in spinal cord injury subjects
de Mello MT et al.. Spinal Cord 34(5) 294-296. (1996)
acute physical activity
Crossover
Number of leg movements (PLM + RLS)— Mean difference -23.0, p=0.03
Favors treatmentRoB: High
A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients
Micah L. Thorp et al.. American Journal of Kidney Diseases 38(1) 104-108. (2001)
gabapentin
CrossoverN = 16
RLS symptom severity questionnaire score (parametric)— Mean difference -2.80, p=0.01
Favors treatmentRoB: Some Concerns
A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome
James A. Sloand et al.. American Journal of Kidney Diseases 43(4) 663-670. (2004)
iron
RCTN = 25
RLS symptom severity score
Favors treatmentRoB: Some Concerns
An Intradialysis Diagnostic Test for Restless Legs Syndrome: A Pilot Study
Akito Kume et al.. American Journal of Kidney Diseases 54(2) 318-326. (2009)
pergolide
Quasi-Experimental
Presence of periodic limb movements (PLMs) on 30-minute SIT during dialysis (diagnostic accuracy)
InconclusiveRoB: High
Rotigotine in Hemodialysis-Associated Restless Legs Syndrome: A Randomized Controlled Trial
Yves Dauvilliers et al.. American Journal of Kidney Diseases 68(3) 434-443. (2016)
rotigotine
RCTN = 30
Periodic Limb Movement Index (PLMI) ratio (end of maintenance to baseline)— Rate ratio 0.44 (0.22–0.88), p=0.02
Favors treatmentRoB: Some Concerns
A Randomized, Open Label, Exploratory Trial Comparing Efficacy of Amantadine and Ropinirole in Restless Legs Syndrome
Govind Madhaw et al.. Sleep Science 16(02) 174-182. (2023)
ropinirole
RCTN = 46
International RLS Study Group Rating Scale (IRLS) score— Mean difference 8.00, p=0.00
Favors treatmentRoB: Some Concerns
Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome
Richard P. Allen et al.. New England Journal of Medicine 370(7) 621-631. (2014)
pregabalin
RCTN = 731
IRLS Study Group Rating Scale score— Mean difference -4.50 (-5.90–-3.20), p=0.00
Favors treatmentRoB: Some Concerns
Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS
William G. Ondo et al.. International Journal of Neuroscience 132(8) 778-782. (2022)
ecopipam
CrossoverN = 10
International Restless Legs Syndrome Rating Scale (IRLS)— Mean difference -2.20
No differenceRoB: Some Concerns
Usefulness of electronic stimulation in restless legs syndrome: a pilot study
Yong Won Cho et al.. International Journal of Neuroscience 132(12) 1225-1228. (2022)
electronic stimulation
RCTN = 48
Visual Analogue Scale for RLS symptoms— Mean difference 2.42, p=0.75
MixedRoB: High
Gabapentin Versus Levodopa for the Treatment of Restless Legs Syndrome in Hemodialysis Patients: An Open‐Label Study
Hasan Micozkadıoglu et al.. Renal Failure 26(4) 393-397. (2004)
gabapentin
CrossoverN = 15
RLS severity score
Favors treatmentRoB: High
Efficacy of an Eight-Week Yoga Intervention on Symptoms of Restless Legs Syndrome (RLS): A Pilot Study
Kim E. Innes et al.. The Journal of Alternative and Complementary Medicine 19(6) 527-535. (2013)
yoga
Quasi-ExperimentalN = 13
International RLS Rating Scale (IRLS) Total Score— Mean difference -10.3, p=0.01
InconclusiveRoB: High
The Effect of Cannabidiol for Restless Legs Syndrome/Willis-Ekbom Disease in Parkinson's Disease Patients with REM Sleep Behavior Disorder: A
Post Hoc
Exploratory Analysis of Phase 2/3 Clinical Trial
Carlos Mauricio Oliveira de Almeida et al.. Cannabis & Cannabinoid Research 8(2) 374-378. (2023)
cannabidiol
RCTN = 18
RLS/WED severity by IRLSSG rating scale
No differenceRoB: Some Concerns
An Exploratory Randomized Controlled Trial of a 12-Week Yoga Versus Educational Film Program for the Management of Restless Legs Syndrome: Feasibility and Acceptability
Terry Kit Selfe et al.. Journal of Integrative and Complementary Medicine 28(4) 309-319. (2022)
yoga
RCTN = 41
Class attendance rate
InconclusiveRoB: Some Concerns
Efficacy and Safety of Acupuncture for Restless Legs Syndrome in Patients with End-Stage Renal Disease: A Randomized-Controlled Trial at Hospital-Based Hemodialysis Center
Jia-Ming Chen et al.. Journal of Integrative and Complementary Medicine 30(10) 978-985. (2024)
acupuncture
RCTN = 41
International Restless Legs Syndrome Rating Scale (IRLSRS)— Mean difference -3.20, p=0.00
Favors treatmentRoB: Some Concerns
A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome
Giannaki CD et al.. Nephrology Dialysis Transplantation 28(11) 2834-2840. (2013)
progressive aerobic exercise training
RCTN = 24
RLS symptom severity (IRLS score)— Mean difference -11.1, p=0.02
Favors treatmentRoB: Some Concerns
Successful Treatment of the Idiopathic Restless Legs Syndrome in a Randomized Double-Blind Trial of Oxycodone Versus Placebo
Arthur S. Walters et al.. Sleep 16(4) 327-332. (1993)
oxycodone
CrossoverN = 11
Leg sensations (paresthesias) - subjective daily rating— Mean difference -1.32, p=0.01
Favors treatmentRoB: Some Concerns
L-Dopa Therapy of Uremic and Idiopathic Restless Legs Syndrome: A Double-Blind, Crossover Trial
Trenkwalder C. et al.. Sleep 18(8) 681-688. (1995)
levodopa
CrossoverN = 28
Frequency of PLM (polysomnography, total night)— Mean difference -132, p=0.00
Favors treatmentRoB: Some Concerns
Randomized, Double-Blind, Placebo-Controlled Study of Clonidine in Restless Legs Syndrome
Wagner ML et al.. Sleep 19(1) 52-8. (1996)
clonidine
CrossoverN = 10
Paresthesias (leg sensations) subjective rating— Mean difference -1.40, p=0.02
Favors treatmentRoB: Some Concerns
10.1093/sleep/19.3.214
levodopa/carbidopa
CrossoverN = 8
Leg movements per hour of sleep (LM Index)— Mean difference -40.0, p=0.01
Favors treatmentRoB: Some Concerns
Effect of Pergolide on Restless Legs and Leg Movements in Sleep in Uremic Patients
Jacek Pieta et al.. Sleep 21(6) 617-622. (1998)
pergolide
CrossoverN = 14
Percentage of first hour in bed with increased leg EMG activity (PSG)— Mean difference -8.60, p=0.05
No differenceRoB: Some Concerns
Rapid Onset of Action of Levodopa in Restless Legs Syndrome: A Double-Blind, Randomized, Multicenter, Crossover Trial
Heike Beneš et al.. Sleep 22(8) 1073-1081. (1999)
levodopa/benserazide
CrossoverN = 35
PLMs per hour in bed— Mean difference -26.8, p=0.00
Favors treatmentRoB: Some Concerns
10.1093/sleep/23.3.1b
cabergoline
Quasi-Experimental
Number of Periodic Leg Movements (PLM) during time in bed— Mean difference -169, p=0.00
InconclusiveRoB: High
Cabergoline is an Effective Single-drug Treatment for Restless Legs Syndrome: Clinical and Actigraphic Evaluation
Marco Zucconi et al.. Sleep 26(7) 815-818. (2003)
cabergoline
Quasi-ExperimentalN = 12
International RLS Study Group Rating Scale score— Mean difference -11.8, p=0.01
Favors treatmentRoB: High
Long-term Safety and Efficacy of Cabergoline for the Treatment of Idiopathic Restless Legs Syndrome: Results from an Open-Label 6-Month Clinical Trial
Heike Beneš et al.. Sleep 27(4) 674-682. (2004)
cabergoline
Quasi-Experimental
Severity of RLS during the night (RLS-6 scale)
InconclusiveRoB: High
Ropinirole Decreases Periodic Leg Movements and Improves Sleep Parameters in Patients with Restless Legs Syndrome
Allen R. et al.. Sleep 27(5) 907-914. (2004)
ropinirole
RCTN = 65
Periodic limb movements of sleep per hour (PLMS/hour)— Mean difference -27.2 (-39.1–-15.4), p=0.00
Favors treatmentRoB: Some Concerns
A Randomized, Double-Blind, Placebo-Controlled, Crossover Study of Xp13512/Gsk1838262 in the Treatment of Patients With Primary Restless Legs Syndrome
Kushida CA et al.. Sleep 32(2) 159-168. (2009)
xp13512 (gabapentin enacarbil)
CrossoverN = 38
Change from baseline IRLS total score at Day 14— Mean difference -10.2, p=0.00
Favors treatmentRoB: Some Concerns
Acute Dopamine-Agonist Treatment in Restless Legs Syndrome: Effects on Sleep Architecture and NREM Sleep Instability
Raffaele Ferri et al.. Sleep 33(6) 793-800. (2010)
pramipexole
RCTN = 34
Periodic Leg Movements during Sleep (PLMS) Index— Mean difference -46.5
Favors treatmentRoB: Some Concerns
10.1093/sleep/9.3.385
clonazepam and temazepam
CrossoverN = 10
Sleep latency— Mean difference -9.30
Favors treatmentRoB: Some Concerns
0791 Effects of Low Frequency Electrical Stimulators as Nonpharmacological Treatment in Restless Legs Syndrome
Y Cho et al.. Sleep 43(Supplement_1) A301-A301. (2020)
low frequency electrical stimulators
RCTN = 46
RLS symptom severity
Favors treatmentRoB: High
0796 Dipyridamole for the Treatment of RLS: Preliminary Results of a Cross-Over, Placebo-Controlled, Double-Blind Trial
Diego Garcı́a-Borreguero et al.. Sleep 43(Supplement_1) A303-A303. (2020)
dipyridamole
CrossoverN = 15
IRLS total score (International Restless Legs Syndrome rating scale)— Mean difference -6.82, p=0.05
No differenceRoB: Some Concerns
0802 To Examine the Effect of Gabapentin Enacarbil in Primary Restless Legs Syndrome Patients Who are on Dopaminergic Agents and Exhibiting Augmentation
Pradeep C. Bollu et al.. Sleep 43(Supplement_1) A305-A305. (2020)
gabapentin enacarbil
Quasi-Experimental
Augmentation Severity Rating Scale (ASRS)
Favors treatmentRoB: High
0809 A Randomized Double-blind, Placebo Controlled Trial With Cross-over, To Assess The Efficacy Of Correcting Vitamin D Deficiency In Improving The Symptoms Of Restless Legs Syndrome (RLS)
Jennie Wong et al.. Sleep 43(Supplement_1) A307-A308. (2020)
vitamin d3
CrossoverN = 2
RLS symptom severity (weekly iRLS questionnaire)
InconclusiveRoB: Some Concerns
531 Efficacy of a physical activity intervention for managing restless legs syndrome in multiple sclerosis: A pilot RCT
Katie Cederberg et al.. Sleep 44(Supplement_2) A209-A209. (2021)
physical activity intervention
RCTN = 15
Overall RLS severity
Favors treatmentRoB: Some Concerns
0710 Effects of tonic motor activation (TOMAC) therapy on sleep quality for refractory restless legs syndrome
Richard Bogan et al.. SLEEP 46(Supplement_1) A311-A312. (2023)
tonic motor activation (tomac) therapy
RCTN = 133
MOS-Sleep Sleep Problems Index I (MOS-I)— Mean difference -9.00, p=0.00
Favors treatmentRoB: Some Concerns
0713 Long-term response to tonic motor activation (TOMAC) therapy for refractory restless legs syndrome
Asim Roy et al.. SLEEP 46(Supplement_1) A313-A313. (2023)
tonic motor activation (tomac)
RCTN = 133
Clinician Global Impressions-Improvement (CGI-I) responder rate
InconclusiveRoB: Some Concerns
Change of iron content in brain regions after intravenous iron therapy in restless legs syndrome: quantitative susceptibility mapping study
Tae-Joon Kim et al.. SLEEP 46(8) zsad154. (2023)
iron
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLS)— Mean difference -10.2, p=0.00
Favors treatmentRoB: High
Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study
Roy A. et al.. SLEEP 46(10) zsad188. (2023)
tonic motor activation (tomac)
Quasi-Experimental
Clinical Global Impressions-Improvement (CGI-I) Responder Rate
Favors treatmentRoB: High
Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial
Bogan RK et al.. SLEEP 46(10) zsad190. (2023)
tonic motor activation (tomac)
RCTN = 133
Clinical Global Impressions-Improvement (CGI-I) responder rate at Week 4— Risk difference 0.28 (0.14–0.43), p=0.00
Favors treatmentRoB: Low
0390 Efficacy of Suvorexant for Insomnia Disorder in Well-controlled Restless Legs Syndrome
John Winkelman et al.. SLEEP 47(Supplement_1) A167-A168. (2024)
suvorexant
CrossoverN = 34
Actigraphically-derived Total Sleep Time (TST)
No differenceRoB: Some Concerns
0687 RLS Treatment Reduces Nighttime Agitation and Increases Sleep Duration in Older Adults with Alzheimer's Disease
Kathy Richards et al.. SLEEP 47(Supplement_1) A294-A295. (2024)
gabapentin enacarbil
RCTN = 147
Nighttime agitation— Mean difference -2.21, p=0.00
Favors treatmentRoB: Some Concerns
0704 Comparative Efficacy of Tonic Motor Activation for Medication-Naïve and Dopaminergic-Treated Restless Legs Syndrome
Mark Buchfuhrer et al.. SLEEP 47(Supplement_1) A301-A301. (2024)
tonic motor activation (tomac)
RCT
International RLS Scale (IRLS) score change — Trial 1 (crossover), drug-naive subgroup— Mean difference -4.20, p=0.01
Favors treatmentRoB: Some Concerns
0712 Tonic Motor Activation for Restless Legs Syndrome Is Compatible with Sleep Onset and Reduces Periodic Leg Movements
Stephanie Rigot et al.. SLEEP 47(Supplement_1) A304-A305. (2024)
tonic motor activation (tomac)
Quasi-ExperimentalN = 23
Periodic leg movements during sleep (PLMS) frequency— Mean difference -27.6, p=0.01
Favors treatmentRoB: High
0903 Sex-Related Differences in Periodic Leg Movements Across the Lifespan and in Their Response to Treatment in RLS
Maria Mogavero et al.. SLEEP 48(Supplement_1) A392-A392. (2025)
pramipexole and ropinirole
Quasi-ExperimentalN = 41
Total leg movements
InconclusiveRoB: High
0664 The Effect Of Gabapentin Enacarbil On Dopaminergic Augmentation In Patients With Primary Restless Legs Syndrome
M. Goyal et al.. Sleep 41(suppl_1) A246-A246. (2018)
gabapentin enacarbil
Quasi-Experimental
International Restless Legs Syndrome Rating Scale (IRLS) score
InconclusiveRoB: High
Striatal histamine mechanism in the pathogenesis of restless legs syndrome
Yuan-Yang Lai et al.. Sleep 43(2) zsz223. (2019)
thioperamide
Quasi-Experimental
Periodic Leg Movements in Sleep index (PLMSI) - 8-hour post-injection
InconclusiveRoB: High
0747 cranial electrotherapy for military beneficiaries with restless leg syndrome
TL Yost et al.. Sleep 40(suppl_1) A277-A277. (2017)
cranial electrical stimulation
Crossover
International Restless Legs Syndrome Scale (IRLS) — change from baseline— Mean difference -11.1, p=0.00
Favors treatmentRoB: Some Concerns
Restless Legs Syndrome Treatment with Dopaminergic Drugs
Levket Akpinar. Clinical Neuropharmacology 10(1) 69-79. (1987)
levodopa/benserazide
—
Exercise Mediates The Association Between Sleep Quality And Restless Legs Syndrome Severity
Melissa M. Aukerman et al.. Medicine & Science in Sports & Exercise 37(Supplement) S127. (2005)
aerobic and resistance exercise
RCT
—
Ropinirole as a Treatment of Restless Legs Syndrome in Patients on Chronic Hemodialysis
Maria Teresa Pellecchia et al.. Clinical Neuropharmacology 27(4) 178-181. (2004)
ropinirole
RCT
—
The Effect of Cold Dialysis in Motor and Sensory Symptoms of RLS/WED Occurring During Hemodialysis: A Double-Blind Study
Giorgos K. Sakkas et al.. ASAIO Journal 64(1) 110-114. (2018)
cold dialysis
—
Intradialytic Aerobic Exercise Training Ameliorates Symptoms of Restless Legs Syndrome and Improves Functional Capacity in Patients on Hemodialysis
Giorgos K. Sakkas et al.. ASAIO Journal 54(2) 185-190. (2008)
aerobic exercise training
—
Non-Pharmacological Management of Periodic Limb Movements During Hemodialysis Session in Patients With Uremic Restless Legs Syndrome
Christoforos D. Giannaki et al.. ASAIO Journal 56(6) 538-542. (2010)
exercise (cycling)
—
Effects of acupuncture on sensory symptoms and motor signs in patients with restless legs syndrome: A crossover randomized controlled trial
Takero Fukutome et al.. Medicine 101(51) e32317. (2022)
acupoint injection
CrossoverN = 8
Mean Leg Discomfort Score (MLDS) during SIT— Mean difference -42.4 (-59.2–-19.8), p=0.00
MixedRoB: Some Concerns
Hydrotherapy and acupressure in restless legs syndrome: A randomized, controlled, 3-armed, explorative clinical trial
Julia Kubasch et al.. Medicine 102(26) e34046. (2023)
hydrotherapy and acupressure
RCTN = 51
RLS Symptom Severity (International Restless Legs Syndrome Study Group Rating Scale)
InconclusiveRoB: High
Effect of “He Tiao Du Ren An Shen Acupuncture” on restless leg syndrome: A randomized trial
Xin-Rui Guan et al.. Medicine 103(39) e39926. (2024)
acupuncture (he tiao du ren an shen)
RCTN = 66
International Restless Leg Syndrome Scale (IRLS) score— Mean difference -0.30, p=0.85
No differenceRoB: Some Concerns
Sequential Compression Devices for Treatment of Restless Legs Syndrome
Arn H. Eliasson et al.. Medicine 86(6) 317-323. (2007)
pneumatic sequential compression devices
Quasi-Experimental
RLS Severity (International RLS Study Group Rating Scale)— Mean difference -16.0, p=0.00
InconclusiveRoB: High
Entacapone Prolongs the Reduction of PLM by Levodopa/Carbidopa in Restless Legs Syndrome
Olli Polo et al.. Clinical Neuropharmacology 30(6) 335-344. (2007)
levodopa/carbidopa/entacapone
CrossoverN = 28
Periodic limb movements per hour during total sleep time (PLM/h TST)— Mean difference -13.1, p=0.05
No differenceRoB: Some Concerns
Patient- and Physician-Rated Measures Demonstrate the Effectiveness of Ropinirole in the Treatment of Restless Legs Syndrome
Clete A. Kushida et al.. Clinical Neuropharmacology 31(5) 281-286. (2008)
ropinirole
RCTN = 362
Change from baseline in IRLS total score— Mean difference -4.11 (-6.08–-2.14), p=0.00
Favors treatmentRoB: Some Concerns
Gabapentin Enacarbil in Restless Legs Syndrome
Arthur S. Walters et al.. Clinical Neuropharmacology 32(6) 311-320. (2009)
gabapentin enacarbil
RCTN = 95
Change from baseline IRLS total score at day 14 (end of treatment)— Mean difference -7.20, p=0.00
Favors treatmentRoB: Some Concerns
Dopaminergic Treatment in Idiopathic Restless Legs Syndrome
Ulf Kallweit et al.. Clinical Neuropharmacology 33(6) 276-278. (2010)
pramipexole
CrossoverN = 37
Epworth Sleepiness Scale (ESS) score
No differenceRoB: Some Concerns
A 52-Week Study of Gabapentin Enacarbil in Restless Legs Syndrome
Aaron L. Ellenbogen et al.. Clinical Neuropharmacology 34(1) 8-16. (2011)
gabapentin enacarbil
Quasi-Experimental
International Restless Legs Scale (IRLS) total score - change from parent study baseline
InconclusiveRoB: High
A Randomized, Double-Blind, Placebo-Controlled, Dose-Response Study to Assess the Pharmacokinetics, Efficacy, and Safety of Gabapentin Enacarbil in Subjects With Restless Legs Syndrome
Ritu Lal et al.. Clinical Neuropharmacology 35(4) 165-173. (2012)
gabapentin enacarbil
RCTN = 217
IRLS Rating Scale total score change from baseline at week 12— Mean difference -4.50
InconclusiveRoB: Some Concerns
Influence of Cabergoline on Motor Excitability in Patients With Restless Legs Syndrome
Gorsler A. et al.. Journal of Clinical Neurophysiology 24(6) 456-460. (2007)
cabergoline
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLSSGRS)
Favors treatmentRoB: High
Comparison the effect of valerian and gabapentin on RLS and sleep quality in hemodialysis patients: A randomized clinical trial
Iman Hajizadeh et al.. Therapeutic Apheresis and Dialysis 27(4) 621-628. (2023)
gabapentin
CrossoverN = 40
Restless Legs Syndrome severity score— Mean difference 0.12, p=0.96
No differenceRoB: High
Comparison of the efficacies of oral iron and pramipexole for the treatment of restless legs syndrome patients with low serum ferritin
Lee CS et al.. European Journal of Neurology 21(2) 260-266. (2014)
pramipexole
RCTN = 30
International RLS Study Group Rating Scale for Severity (IRLS) score— Mean difference -0.40, p=0.99
No differenceRoB: High
Carbamazepine Therapy in Restless Legs: Discrimination between Responders and Non‐responders
Larsen S. et al.. Acta Medica Scandinavica 218(2) 223-227. (1985)
carbamazepine
RCTN = 174
Frequency of restless legs attacks per week
InconclusiveRoB: Some Concerns
High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron
Birgegård G. et al.. Vox Sanguinis 99(4) 354-361. (2010)
iron
RCTN = 120
P-ferritin (all subjects)— Mean difference 7.20, p=0.00
Favors treatmentRoB: Some Concerns
Periodic Leg Movements in Sleep with Restless Legs Syndrome: Effect of Clonazepam Treatment
Jun Horiguchi et al.. Psychiatry and Clinical Neurosciences 46(3) 727-732. (1992)
clonazepam
Quasi-Experimental
Total number of periodic leg movements in sleep (left leg)
No differenceRoB: High
Actometry in measuring the symptom severity of restless legs syndrome
Tuisku K. et al.. European Journal of Neurology 12(5) 385-387. (2005)
pramipexole
Quasi-Experimental
Nocturnal lower-limb activity
InconclusiveRoB: High
The powerful pre‐treatment effect: placebo responses in restless legs syndrome trials
de la Fuente-Fernández R.. European Journal of Neurology 19(10) 1305-1310. (2012)
rotigotine
RCT
Change in IRLS sum score from baseline to end of maintenance (placebo arm, pre-treated patients, SP790)
Favors treatmentRoB: Some Concerns
Orphenadrine citrate (norflex) for the treatment of “restless legs” and related syndromes
Roy J. Popkin. Journal of the American Geriatrics Society 19(1) 76-79. (1971)
orphenadrine citrate
Quasi-Experimental
Overall symptomatic response to orphenadrine citrate
InconclusiveRoB: High
Clonazepam and vibration in restless legs syndrome
Pasquale Montagna et al.. Acta Neurologica Scandinavica 69(6) 428-430. (1984)
clonazepam
CrossoverN = 6
Quality of sleep (week-score)
No differenceRoB: Some Concerns
Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome
Nardone R. et al.. Acta Neurologica Scandinavica 114(4) 244-249. (2006)
cabergoline
Quasi-Experimental
Short Latency Intracortical Inhibition (SICI)— Mean difference 31.0, p=0.03
InconclusiveRoB: High
PTPRD as a candidate druggable target for therapies for restless legs syndrome?
Milca A. Morais et al.. Journal of Sleep Research 30(4) e13216. (2021)
pramipexole
Quasi-ExperimentalN = 16
Total Sleep Time (TST)— Mean difference 32.5, p=0.01
Favors treatmentRoB: High
Transcutaneous electrical nerve stimulation in the management of restless legs syndrome symptoms: A single‐blind, parallel‐group clinical study
Zeynep Selcan Şanli et al.. Journal of Sleep Research 33(5) e14167. (2024)
pramipexole
RCTN = 50
International Restless Legs Syndrome Rating Scale (IRLSRS)— Mean difference -3.18, p=0.03
Favors treatmentRoB: Some Concerns
Sex‐based disparities in dopamine agonist response in patients with restless legs syndrome
Maria P. Mogavero et al.. Journal of Sleep Research 34(2) e14311. (2025)
pramipexole and ropinirole
Quasi-ExperimentalN = 41
PLMS index (periodic leg movements during sleep index)— Mean difference -13.4, p=0.00
InconclusiveRoB: High
Treatment of the restless legs syndrome with carbamazepine: a double blind study.
Telstad W. et al.. BMJ 288(6415) 444-446. (1984)
carbamazepine
RCTN = 174
Severity of symptoms of restless legs syndrome
Favors treatmentRoB: Some Concerns
Restless legs syndrome in patients with type 2 diabetes: effectiveness of pramipexole therapy
Shin-Ichi Harashima et al.. BMJ Supportive & Palliative Care 6(1) 89-93. (2016)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Rating Scale (IRLS) score
InconclusiveRoB: High
Apomorphine in idiopathic restless legs syndrome: an exploratory study
Tribl GG et al.. Journal of Neurology, Neurosurgery & Psychiatry 76(2) 181-185. (2005)
apomorphine
CrossoverN = 9
Subjective leg symptoms (visual analogue scale)— Mean difference -3.20, p=0.01
Favors treatmentRoB: High
Cognitive behavioural group therapy to improve patients' strategies for coping with restless legs syndrome: a proof-of-concept trial
Hornyak M. et al.. Journal of Neurology, Neurosurgery & Psychiatry 79(7) 823-825. (2008)
cognitive behavioural therapy
Quasi-Experimental
Quality of Life in Restless Legs Syndrome (QoL-RLS) total score— Mean difference -5.20, p=0.00
InconclusiveRoB: High
Response to ropinirole in restless legs syndrome is independent of baseline serum ferritin
Morgan JC et al.. Journal of Neurology, Neurosurgery & Psychiatry 79(8) 964-965. (2008)
ropinirole
RCTN = 550
Change from baseline in International Restless Legs Scale (IRLS) total score at week 12 LOCF— Mean difference -2.80 (-5.40–-0.20), p=0.04
Favors treatmentRoB: Some Concerns
The Effects of a Gentle Yoga Program on Sleep, Mood, and Blood Pressure in Older Women with Restless Legs Syndrome (RLS): A Preliminary Randomized Controlled Trial
Kim E. Innes et al.. Evidence-Based Complementary and Alternative Medicine 2012 1-14. (2012)
gentle yoga
RCTN = 20
Pittsburgh Sleep Quality Index - Global Score— Std. mean difference 2.59, p=0.01
Favors treatmentRoB: Some Concerns
Aerobic Exercise Improves Signs of Restless Leg Syndrome in End Stage Renal Disease Patients Suffering Chronic Hemodialysis
Mojgan Mortazavi et al.. The Scientific World Journal 2013(1) 628142. (2013)
aerobic exercise
RCTN = 26
Restless leg syndrome severity score— Mean difference -4.97, p=0.00
Favors treatmentRoB: High
Actigraph Evaluation of Acupuncture for Treating Restless Legs Syndrome
Weidong Pan et al.. Evidence-Based Complementary and Alternative Medicine 2015 1-7. (2015)
acupuncture
RCTN = 38
Nocturnal Activity (NA) — leg actigraph zero-crossing counts during all nocturnal bedtime
No differenceRoB: High
Effect of Local Warm Compression on Restless Leg Syndrome and Fatigue among Critical Care Nurses: A Parallel Randomized Clinical Trial
Maryam Ameri et al.. Critical Care Research and Practice 2022 1-7. (2022)
warm compression
RCTN = 120
Restless Legs Syndrome severity— Mean difference 0.78, p=0.41
No differenceRoB: Some Concerns
A Randomized, Double-Blind Placebo-Controlled Trial of Iron in Restless Legs Syndrome
Bradley J. Davis et al.. European Neurology 43(2) 70-75. (2000)
iron
RCTN = 28
Quality of sleep (VAS 1) — improvement (dichotomous)
No differenceRoB: Some Concerns
Sleep Laboratory Studies in Restless Legs Syndrome Patients as Compared with Normals and Acute Effects of Ropinirole
Saletu M. et al.. Neuropsychobiology 41(4) 190-199. (2000)
ropinirole
CrossoverN = 12
PLM per hour of total sleep time (PLM/h TST)— Mean difference -29.4, p=0.01
Favors treatmentRoB: High
Clinical Data on Restless Legs Syndrome: A Dose-Finding Study with Cabergoline
Karin Stiasny. European Neurology 46(Suppl. 1) 24-26. (2001)
cabergoline
RCTN = 86
Severity of RLS symptoms at night (primary endpoint)
InconclusiveRoB: Some Concerns
Low-Dose Pramipexole in the Management of Restless Legs Syndrome
Karin Stiasny-Kolster et al.. Neuropsychobiology 50(1) 65-70. (2004)
pramipexole
Quasi-Experimental
IRLS Severity Scale (global RLS severity)— Mean difference -22.5, p=0.00
InconclusiveRoB: High
The Acute Effect of a Low Dosage of Pramipexole on Severe Idiopathic Restless Legs Syndrome: An Open-Label Trial
Giovanni Merlino et al.. Neuropsychobiology 54(3) 195-200. (2006)
pramipexole
CrossoverN = 10
Visual Analog Scale for RLS sensory symptoms— Mean difference -5.80, p=0.00
Favors treatmentRoB: High
Excessive Daytime Sleepiness in Idiopathic Restless Legs Syndrome: Characteristics and Evolution under Dopaminergic Treatment
Ulf Kallweit et al.. European Neurology 62(3) 176-179. (2009)
dopaminergic agents
Quasi-Experimental
International RLS Study Group Rating Scale (IRLS) score— Mean difference -7.30, p=0.00
Favors treatmentRoB: High
Efficacy, Safety and Dose-Response of Pramipexole in Japanese Patients with Primary Restless Legs Syndrome: Randomized Trial
Yuichi Inoue et al.. Neuropsychobiology 63(1) 35-42. (2011)
pramipexole
RCTN = 154
IRLS Total Score— Mean difference 0.20
No differenceRoB: Some Concerns
Investigating Homeopathic Verum and Placebo Globules with UV Spectroscopy
Sabine D. Klein et al.. Complementary Medicine Research 20(4) 295-297. (2013)
calcium carbonate / quercus e cortice 6x
RCT
UV absorbance at 200-290 nm (corrected average)
InconclusiveRoB: High
Lack of Pharmacokinetic Interactions Between Transdermal Rotigotine and Oral Levodopa/Carbidopa
Marina Braun et al.. The Journal of Clinical Pharmacology 49(9) 1047-1055. (2009)
rotigotine
CrossoverN = 24
Levodopa AUC at steady state (AUCss)— Odds ratio 0.97
InconclusiveRoB: Some Concerns
Population Pharmacokinetics and Pharmacodynamics of Gabapentin After Administration of Gabapentin Enacarbil
Ritu Lal et al.. The Journal of Clinical Pharmacology 53(1) 29-40. (2013)
gabapentin enacarbil
RCTN = 994
Change from baseline in IRLS total score at week 12/end of treatment— Mean difference -6.16
Favors treatmentRoB: Some Concerns
Clinical and electrophysiological impact of repetitive low-frequency transcranial magnetic stimulation on the sensory–motor network in patients with restless legs syndrome
Giuseppe Lanza et al.. Therapeutic Advances in Neurological Disorders 11 1756286418759973. (2018)
repetitive transcranial magnetic stimulation (rtms)
CrossoverN = 23
Subjective quality of initiating and maintaining sleep
InconclusiveRoB: Some Concerns
Effect of Oral Iron Administration on Mental State in Children With Low Serum Ferritin Concentration
Katsunaka Mikami et al.. Global Pediatric Health 6 2333794X19884816. (2019)
iron
Quasi-Experimental
Clinical Global Impression Severity (CGI)
Favors treatmentRoB: High
A randomized controlled pilot trial of positional release manipulation (counterstrain) in the treatment of restless legs syndrome
Roderic MacDonald et al.. International Musculoskeletal Medicine 33(1) 21-25. (2011)
counterstrain manipulation
RCTN = 40
International Restless Legs Study Group Severity Scale
InconclusiveRoB: High
Counterstrain manipulation in the treatment of restless legs syndrome: A pilot single-blind randomized controlled trial; the CARL Trial
Theo Peters et al.. International Musculoskeletal Medicine 34(4) 136-140. (2012)
counterstrain manipulation
RCTN = 39
International Restless Legs Scale (IRLS) total score change from baseline to week 6— Mean difference -8.06 (-13.0–-3.15), p=0.00
Favors treatmentRoB: Some Concerns
Comparison of the bioavailability and adhesiveness of different rotigotine transdermal patch formulations
Jan-Peer Elshoff et al.. Current Medical Research and Opinion 29(12) 1657-1662. (2013)
rotigotine
Crossover
Bioequivalence: AUC(0-tz) ratio of unconjugated rotigotine plasma concentrations
InconclusiveRoB: Some Concerns
Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study
Diego Garcia-Borreguero et al.. Current Medical Research and Opinion 32(1) 77-85. (2016)
rotigotine
RCTN = 150
International Restless Legs Syndrome Rating Scale (IRLS) sum score— Mean difference -0.27 (-2.96–2.42), p=0.85
No differenceRoB: Some Concerns
Effect of exercise training and dopamine agonists in patients with uremic restless legs syndrome: a six-month randomized, partially double-blind, placebo-controlled comparative study
Christoforos D. Giannaki et al.. BMC Nephrology 14(1) 194. (2013)
ropinirole
RCTN = 32
RLS symptom severity (IRLS score)— Mean difference -12.0, p=0.01
Favors treatmentRoB: Some Concerns
Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch
Birgit Högl et al.. BMC Neurology 10(1) 86. (2010)
rotigotine
Quasi-Experimental
International RLS Study Group Severity Rating Scale total score (IRLS)
InconclusiveRoB: High
OA14.03. Effects of yoga on sleep, mood, and related outcomes in older women with Restless Legs Syndrome: a nested randomized controlled trial (RCT)
Kim Innes et al.. BMC Complementary and Alternative Medicine 12(S1) O55-O55. (2012)
yoga
RCTN = 20
Sleep quality
No differenceRoB: High
P02.156. Effects of a gentle yoga program on Restless Legs Syndrome (RLS) symptoms and related outcomes in women with RLS: a pilot study
Kim E. Innes et al.. BMC Complementary and Alternative Medicine 12(S1) P212-P212. (2012)
gentle yoga
Quasi-Experimental
RLS symptoms overall
InconclusiveRoB: High
Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial
Mark J. Buchfuhrer et al.. BMC Neurology 23(1) 415. (2023)
tonic motor activation (tomac)
Quasi-Experimental
Proportion of participants completing step-down 1 with CGI-I score <=5 and actual opioid dose reduction >=20%
InconclusiveRoB: High
Effect of dairy products fortified with vitamin d3 on restless legs syndrome in women with premenstrual syndrome, abdominal obesity and vitamin d deficiency: a pilot study
Payam Sharifan et al.. BMC Women's Health 24(1) 434. (2024)
vitamin d3
RCTN = 141
Restless Legs Syndrome score (overall, all participants)
No differenceRoB: Some Concerns
Therapeutic effects of magnesium and vitamin B6 in alleviating the symptoms of restless legs syndrome: a randomized controlled clinical trial
Ali Jadidi et al.. BMC Complementary Medicine and Therapies 23(1) 1. (2022)
magnesium and vitamin b6
RCTN = 75
Pittsburgh Sleep Quality Index (PSQI)— Mean difference 1.68, p=0.70
No differenceRoB: High
Ropinirole for restless legs syndrome
Adler CH et al.. Neurology 62(8) 1405-1407. (2004)
ropinirole
CrossoverN = 22
RLS Rating Scale score— Mean difference -12.0 (-17.0–-6.30), p=0.00
Favors treatmentRoB: Some Concerns
Efficacy of pergolide in treatment of restless legs syndrome
Trenkwalder C. et al.. Neurology 62(8) 1391-1397. (2004)
pergolide
RCTN = 100
PLMS arousal index (periodic limb movements during sleep with arousals per hour of total sleep time)— Mean difference -9.00, p=0.00
MixedRoB: Some Concerns
Effective cabergoline treatment in idiopathic restless legs syndrome
Stiasny-Kolster K. et al.. Neurology 63(12) 2272-2279. (2004)
cabergoline
RCTN = 86
RLS-6 Scale: Severity of RLS symptoms during the night— Mean difference 2.45 (0.65–4.25), p=0.01
Favors treatmentRoB: Some Concerns
Efficacy of cabergoline in restless legs syndrome
Oertel WH et al.. Neurology 67(6) 1040-1046. (2006)
cabergoline
RCTN = 43
Periodic leg movements during sleep arousal index (PLMS-AI)— Mean difference -13.1 (-21.3–-5.00), p=0.00
Favors treatmentRoB: Some Concerns
Low-dose hydrocortisone in the evening modulates symptom severity in restless legs syndrome
Hornyak M. et al.. Neurology 70(18) 1620-1622. (2008)
hydrocortisone
CrossoverN = 10
Sensory leg discomfort (SLD) during Suggested Immobilization Test
Favors treatmentRoB: Some Concerns
Double-blind, placebo-controlled, pilot trial of botulinum toxin a in restless legs syndrome
Fatta B. Nahab et al.. Neurology 71(12) 950-951. (2008)
botulinum toxin a
CrossoverN = 6
Mean change in IRLS from baseline at 4 weeks postinjection— Mean difference 4.00, p=0.06
No differenceRoB: Some Concerns
Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS
Kushida CA et al.. Neurology 72(5) 439-446. (2009)
xp13512 (gabapentin enacarbil)
RCTN = 222
IRLS total score - change from baseline— Mean difference -6.00 (-7.90–-4.10), p=0.00
Favors treatmentRoB: Some Concerns
Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome
Axel Bauer et al.. Neurology 86(19) 1785-1793. (2016)
rotigotine
RCTN = 81
Total PLM-associated nocturnal SBP elevations— Mean difference -160 (-213–-107), p=0.00
Favors treatmentRoB: Low
Treatment of restless legs syndrome with pregabalin
Garcia-Borreguero D. et al.. Neurology 74(23) 1897-1904. (2010)
pregabalin
RCTN = 58
International Restless Legs Scale (IRLS) total score— Mean difference -5.26, p=0.00
Favors treatmentRoB: Some Concerns
Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome
Manconi M. et al.. Neurology 77(2) 110-117. (2011)
pramipexole
RCTN = 45
Visual Analogue Scale for RLS symptom severity (previous night leg/arm discomfort)— Mean difference -4.10
Favors treatmentRoB: High
2012 Emerging Science Abstracts
Neurology 79(11) 87-91. (2012)
pregabalin
RCTN = 719
International RLS Study Group Rating Scale (IRLS) score change from baseline— Mean difference -4.50, p=0.00
Favors treatmentRoB: Some Concerns
Pramipexole Alleviates Sensory and Motor Symptoms of Restless Legs Syndrome
Jacques Montplaisir et al.. Neurology 51(1) 311-312. (1998)
pramipexole
CrossoverN = 10
Periodic Leg Movement during Sleep (PLMS) index— Mean difference -63.8, p=0.01
Favors treatmentRoB: Some Concerns
Encouraging initial response of restless legs syndrome to pramipexole
Philip M. Becker et al.. Neurology 51(4) 1221-1223. (1998)
pramipexole
Quasi-Experimental
Restless Legs Syndrome Rating Scale (RLSRS) total score— Mean difference -9.20, p=0.00
Favors treatmentRoB: High
Randomized, double-blind, placebo-controlled trial of pergolide in restless legs syndrome
Christopher J. Earley et al.. Neurology 51(6) 1599-1602. (1998)
pergolide
RCTN = 16
PLMS per hour (periodic limb movements of sleep per hour)
No differenceRoB: Some Concerns
A randomized controlled study of pergolide in patients with restless legs syndrome
Wetter TC et al.. Neurology 52(5) 944-944. (1999)
pergolide
CrossoverN = 30
PLM index (periodic leg movements per hour of time in bed, during sleep and wakefulness)— Mean difference -49.3, p=0.00
Favors treatmentRoB: Some Concerns
Exercise Mediates The Association Between Sleep Quality And Restless Legs Syndrome Severity
Melissa M. Aukerman et al.. Medicine & Science in Sports & Exercise 37(Supplement) S127. (2005)
aerobic and resistance training exercise
RCT
—
Management of Symptoms of Restless Legs Syndrome with Traction Straight Leg Raise: A Pilot Study
Eric M. Dinkins et al.. Medicine & Science in Sports & Exercise 43(5) 903. (2011)
traction straight leg raise
RCT
—RoB: High
Efficacy of Intravenous Iron Sucrose in Hemodialysis Patients with Restless Legs Syndrome (RLS): A Randomized, Placebo-Controlled Study
Yinghui Deng et al.. Medical Science Monitor 23 1254-1260. (2017)
iron
RCTN = 32
IRLS score change from baseline— Mean difference -6.57, p=0.00
Favors treatmentRoB: High
Effect of Self-developed Ye’an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction Combined with Tramadol on TCM Symptom Scores and RLS Severity of patients with Restless Legs Syndrome
Bowen Zhou et al.. Pakistan Journal of Medical Sciences 40(5) 1017-1021. (2024)
tramadol
RCTN = 80
International Restless Legs Scale (IRLS) score— Mean difference -5.23, p=0.05
No differenceRoB: High
Efficacy of neuromuscular electric stimulation versus aerobic exercise on uraemic restless legs syndrome
Manal K. Youssef. International Journal of Therapy and Rehabilitation 26(10) 1-12. (2019)
neuromuscular electric stimulation
RCTN = 60
International Restless Legs Syndrome Study Group Rating Scale score— Mean difference 4.60, p=0.00
Favors treatmentRoB: High
Effect of Pramipexole on Cognitive Functions in Restless Legs Syndrome
Minjik Kim et al.. Journal of Korean Sleep Research Society 11(1) 16-20. (2014)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Severity Scale (IRLS)— Mean difference -14.9, p=0.00
Favors treatmentRoB: High
Effect of governor moxibustion for restless legs syndrome of maintenance hemodialysis:a rando-mized controlled trial
Gao Y. et al.. Zhongguo zhen jiu = Chinese acupuncture & moxibustion 36(6) 597-600. (2016)
governor moxibustion
RCTN = 70
International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score— Mean difference -1.22, p=0.05
No differenceRoB: Some Concerns
Haste makes waste: Decision making in patients with restless legs syndrome with and without augmentation
Beatrice Heim et al.. PLOS ONE 12(4) e0174793. (2017)
dopaminergic agents
Quasi-Experimental
Number of beads drawn before making a decision (drawing behaviour)
InconclusiveRoB: High
Randomized pilot trial for the efficacy of the MMF07 foot massager and heat therapy for restless legs syndrome
Ariane Park et al.. PLOS ONE 15(4) e0230951. (2020)
foot massage and heat therapy
FactorialN = 28
International Restless Legs Severity Scale (IRLSS)— Mean difference -9.00 (-16.3–-1.70), p=0.02
Favors treatmentRoB: Some Concerns
Pneumatic Compression Devices Are an Effective Therapy for Restless Legs Syndrome
Christopher J. Lettieri et al.. Chest 135(1) 74-80. (2009)
pneumatic compression devices
RCTN = 35
International Restless Legs Syndrome Study Group Severity Scale (IRLSSS)— Mean difference -5.70, p=0.01
Favors treatmentRoB: Some Concerns
Rifaximin Improves Restless Legs Syndrome Associated with Small Intestinal Bacterial Overgrowth
Leonard Weinstock. American Journal of Gastroenterology 103 S107. (2008)
rifaximin
—
The Effect of Mindfulness-Based Stress Reduction on Restless Legs Syndrome in Hemodialysis Patients: A Randomized Clinical Trial
Zahra Delshad et al.. Nurse Media Journal of Nursing 12(3) 316-324. (2022)
mindfulness-based stress reduction
RCTN = 60
Severity of Restless Legs Syndrome— Mean difference 0.89 (-1.14–2.91), p=0.05
No differenceRoB: Some Concerns
The effects of foot massage on hemodialysis patients’ sleep quality and restless leg syndrome: a comparison of lavender and sweet orange essential oil topical application
Khodayar Oshvandi et al.. Journal of Complementary and Integrative Medicine 18(4) 843-850. (2021)
foot massage with lavender and sweet orange essential oils
RCT
—RoB: High
Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
Feyza Ustabaş Kahraman et al.. Open Medicine 20(1) 20241125. (2025)
vitamin d
Quasi-Experimental
CSHQ Total Score
No differenceRoB: High
The effect of vibration on the severity of restless legs syndrome in hemodialysis patients
Habibollah Hosseini et al.. Journal of Renal Injury Prevention 6(2) 113-116. (2016)
vibration therapy
Quasi-Experimental
Severity of restless legs syndrome symptoms— Mean difference -6.17, p=0.00
InconclusiveRoB: High
The effects of vibration and massage on severity of symptoms of restless leg syndrome and sleep quality in hemodialysis patients; a randomized cross-over clinical trial
Somayeh Azimpour et al.. Journal of Renal Injury Prevention 8(2) 106-111. (2018)
vibration and massage
CrossoverN = 80
Severity of RLS symptoms— Mean difference -2.68, p=0.00
Favors treatmentRoB: High
Gabapentin for treatment of restless legs syndrome among hemodialysis patients; a pilot study
Seyed Majid Mousavi Movahed et al.. Journal of Nephropharmacology 7(2) 104-109. (2018)
gabapentin
CrossoverN = 21
RLS symptom severity score (standardized questionnaire)— Mean difference 0.35
InconclusiveRoB: Some Concerns
Effect of intravenous vitamin C supplementation on the quality of sleep, itching and restless leg syndrome in patients undergoing hemodialysis; A double-blind randomized clinical trial
Shahdak Dadashpour et al.. Journal of Nephropharmacology 7(2) 131-136. (2018)
intravenous vitamin c
RCTN = 90
Pittsburgh Sleep Quality Index (PSQI) total score
Favors treatmentRoB: High
Effect of transcutaneous electrical nerve stimulation with stretching and exercises in restless leg syndrome among pregnant women
Augustina, S Jenifer et al.. Obstetrics & Gynecology International Journal 11(2). (2020)
transcutaneous electrical nerve stimulation with stretching
Quasi-ExperimentalN = 30
Numeric Pain Rating Scale (NPRS)— Mean difference -2.67, p=0.00
Favors treatmentRoB: High
Use of Potassium Citrate in Restless Leg Syndrome (RLS)
Choudhury Mizanur Rouf. Pharmacy & Pharmacology International Journal 4(4). (2016)
potassium citrate
Quasi-Experimental
RLS severity level (Visual Analogue Scale)
InconclusiveRoB: High
The effect of compression stockings on the complaints well-being and sleep quality of pregnant women with restless legs syndrome: a randomized controlled study
Özlem Kaplan et al.. Revista da Associação Médica Brasileira 70(7) e20240145. (2024)
compression stockings
RCTN = 70
Restless Legs Syndrome Severity Rating Scale (IRLSSG)— Mean difference 0.28, p=0.84
No differenceRoB: Some Concerns
Effect of aerobic exercise and yogasana programme on fatigue and stress in peripheral neuropathy patients with restless leg syndrome
T. Suresh Kumar et al.. International Journal of Physiotherapy and Research 5(4) 2220-2224. (2017)
aerobic exercise and yogasana
Quasi-ExperimentalN = 60
Perceived Stress Scale score— Mean difference 0.53
Favors treatmentRoB: High
The Effect of Massage With Lavender Oil on Restless Leg Syndrome in Hemodialysis Patients: A Randomized Controlled Trial
Sayyed Hossein Hashemi et al.. Nursing and Midwifery Studies 4(4) e29617. (2015)
massage with lavender oil
RCTN = 70
Restless Leg Syndrome severity score— Mean difference -0.49, p=0.76
No differenceRoB: High
Effectiveness of muscle stretching exercise on restless leg syndrome among patients undergoing haemodialysis
Jasvinder Kaur et al.. International Journal of Research in Medical Sciences 2164-2169. (2016)
muscle stretching exercise
Quasi-ExperimentalN = 86
RLS symptom severity score (Restless Legs Syndrome Rating Scale)— Mean difference -0.54, p=0.60
No differenceRoB: High
Clinical aspects and differentiated therapy strategies for idiopathic form of restless legs syndrome
Umida G. Yodgorova et al.. The Bulletin of Contemporary Clinical Medicine 18(2) 24-28. (2025)
iron, vitamin d, vitamin b12, folic acid, magnesium, calcium supplementation
Quasi-ExperimentalN = 51
Plasma 25(OH)D concentration (vitamin D level)— Mean difference 17.8, p=0.00
Favors treatmentRoB: High
Change of International Restless Legs Syndrome Study Group Rating Scale subscales with treatment and placebo: a pilot study
Ulrike Mitchell et al.. Journal of Parkinsonism and Restless Legs Syndrome 27. (2014)
unspecified non-pharmaceutical treatment
Quasi-ExperimentalN = 58
IRLS Total Score— Mean difference -7.20, p=0.00
Favors treatmentRoB: High
Vibration and skin blood flow changes in subjects with restless legs syndrome
Ulrike Mitchell et al.. Journal of Parkinsonism and Restless Legs Syndrome 9. (2014)
whole body vibration
—
Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome
Yanan Zhang et al.. Nature and Science of Sleep Volume 16 431-443. (2024)
pramipexole and gabapentin
Quasi-Experimental
Phase Difference (dynamic cerebral autoregulation)— Mean difference -13.0, p=0.00
InconclusiveRoB: High
Dose Response of Gabapentin Enacarbil versus Placebo in Subjects with Moderate-to-Severe Primary Restless Legs Syndrome
Susan A. VanMeter et al.. CNS Drugs 26(9) 773-780. (2012)
gabapentin enacarbil (horizant)
RCTN = 760
Change from baseline in IRLS total score— Mean difference -4.00, p=0.00
Favors treatmentRoB: Some Concerns
Treatment of Japanese Restless Legs Syndrome Patients with Cabergoline: An Open Clinical Preliminary Trial
Hitoshi Aizawa et al.. Internal Medicine 45(7) 453-455. (2006)
cabergoline
Quasi-Experimental
IRLSSG Rating Scale Version 2.2 total score— Mean difference -14.8, p=0.03
Favors treatmentRoB: High
10.2174/0118746136268741240328062217
neurofeedback
RCTN = 30
Subjective sleep quality (Pittsburgh Sleep Quality Index component)
No differenceRoB: High
Comparison of the effect of cold dialysate versus stretching exercises on severity of restless legs syndrome in patients undergoing hemodialysis: A randomized controlled trial
Azam Zirak Aliabadi et al.. Evidence Based Care Journal 10(3) 14-22. (2020)
cold dialysate and stretching exercises
RCTN = 44
Severity of restless legs syndrome— Mean difference 3.60
No differenceRoB: Some Concerns
Effects of warm and cold footbath on sleep quality in pregnant women with restless legs syndrome
جعفریمنش, هادی et al.. Iranian Journal of Obstetrics, Gynecology and Infertility 26(6) 51-60. (2020)
warm and cold water footbath
RCTN = 80
Pittsburgh Sleep Quality Index total score— Mean difference 0.92, p=0.07
No differenceRoB: Some Concerns
The Effect of Massage and Biochemical Oxidative Stress Determinants in Hemodialysis Patients with Restless Leg Syndrome in Turkish People
Aysel Güven et al.. International Journal of Computational and Experimental Science and Engineering 11(3). (2025)
massage
Quasi-ExperimentalN = 42
Restless Legs Syndrome severity (IRLS scale)
InconclusiveRoB: High
The effect of hot water application in pregnant women with restless legs syndrome: a randomised controlled study
Cossu G. et al.. Authorea, Inc. 2(2) V1. (2021)
hot water immersion
RCT
Restless Legs Syndrome Severity Grading Scale
No differenceRoB: High
Effects of progressive muscle relaxation exercises and relaxation music on the severity of restless legs syndrome and sleep quality during pregnancy: A randomized controlled trial
Cossu G. et al.. Authorea, Inc. 2(2) V1. (2023)
progressive muscle relaxation exercises
RCTN = 67
Severity of Restless Legs Syndrome
InconclusiveRoB: High
Pengaruh Latihan Kekuatan terhadap Restless Legs Syndrome Pasien Hemodialisis
Anggriyana Tri Widianti et al.. Jurnal Keperawatan Padjadjaran 5(1). (2017)
strength training (latihan kekuatan)
Quasi-ExperimentalN = 32
RLS scale (IRLS Scale)— Mean difference -3.16, p=0.04
Favors treatmentRoB: High
The effect of intradialysis stretching exercise on the scale of restless leg syndrome
Ahyar Nur et al.. Journal of Islamic Nursing 3(2) 16. (2018)
stretching exercise
Quasi-ExperimentalN = 20
Restless Legs Syndrome severity scale— Mean difference 0.30, p=0.00
No differenceRoB: High
Clinical Study on Treatment of 39 Cases of Uremic Restless Leg Syndrome by Rouxiujiang Decoction Combined with Acupoint Massage
Hongxia Xie. 2018 International Conference on Biomedical Engineering, Machinery and Earth Science (BEMES 2018). (2018)
rouxiujiang decoction
RCTN = 78
RLS severity score— Mean difference -0.05, p=0.82
No differenceRoB: High
The Effect of Selected Core Stability Exercises on Restless Legs Syndrome and Quality of Life in the Elderly Undergoing Hemodialysis
Mehrdad Bastani et al.. Qom Univ Med Sci J 12(8) 48-58. (2018)
core stability exercises
Quasi-ExperimentalN = 30
Restless legs syndrome severity score— Mean difference -5.70, p=0.00
Favors treatmentRoB: High
Actigraphy as a marker for therapy efficacy in patients with restless legs syndrome against the background of diabetic polyneuropathy
N. P. Tkachuk et al.. Ukrainian Neurological Journal 0(3—4) 46-51. (2018)
pramipexole
RCTN = 43
Periodic Limb Movement Index (PLMI) during sleep measured by actigraphy— Mean difference -2.08, p=0.05
No differenceRoB: High
Pilot Trial of OnabotulinumtoxinA (Botox) in Moderate to Severe Restless Legs Syndrome
Pinky Agarwal et al.. International Journal of Neuroscience 121(11) 622-625. (2011)
onabotulinum toxin a
Quasi-Experimental
International Restless Legs Syndrome Scale (IRLSS)— Mean difference -5.75 (-10.8–-0.67), p=0.03
InconclusiveRoB: High
Comparison of two infrared devices in their effectiveness in reducing symptoms associated with RLS
Mitchell UH et al.. Physiotherapy Theory and Practice 27(5) 352-359. (2011)
near-infrared light
RCTN = 26
International Restless Legs Syndrome Study Group rating scale (IRLS) score— Mean difference 2.30, p=0.31
No differenceRoB: Some Concerns
Restless legs syndrome and near-infrared light: An alternative treatment option
Mitchell UH et al.. Physiotherapy Theory and Practice 27(5) 345-351. (2011)
near-infrared light
RCTN = 34
International RLS Rating Scale (IRLS) score— Mean difference -2.20, p=0.09
No differenceRoB: Some Concerns
Using near infrared light to manage symptoms associated with restless legs syndrome
Guffey JS et al.. Physiotherapy Theory and Practice 32(1) 34-44. (2016)
near-infrared light
Quasi-Experimental
International Restless Legs Syndrome Rating Scale (IRLSRS)— Mean difference 9.70 (6.20–13.2), p=0.00
InconclusiveRoB: High
Effect of Near-Infrared Light Therapy Based on Acupoints on the Severity of Restless Legs Syndrome in Patients Undergoing Hemodialysis: A Single-Blind, Randomized Controlled Trial
Mohammad Mehdi Mohammadi et al.. Clinical Medicine & Research 16(1-2) 1-8. (2018)
near-infrared light therapy
RCTN = 60
RLS severity score— Mean difference -0.40, p=0.50
No differenceRoB: Some Concerns
Exercise and Restless Legs Syndrome: A Randomized Controlled Trial
Aukerman MM et al.. The Journal of the American Board of Family Medicine 19(5) 487-493. (2006)
aerobic exercise and resistance training
RCTN = 41
International RLS Study Group (IRLSSG) severity scale total score— Mean difference -1.90, p=0.46
No differenceRoB: Some Concerns
Bupropion and Restless Legs Syndrome: A Randomized Controlled Trial
Bayard M. et al.. The Journal of the American Board of Family Medicine 24(4) 422-428. (2011)
bupropion
RCTN = 60
IRLSSG severity score— Mean difference -4.40, p=0.03
Favors treatmentRoB: Some Concerns
Novel Exercises for Restless Legs Syndrome: A Randomized, Controlled Trial
Eloise G. Harrison et al.. The Journal of the American Board of Family
Medicine 31(5) 783-794. (2018)
tension and trauma release exercises
RCTN = 18
International Restless Legs Syndrome Rating Scale (IRLS) score— Mean difference -2.80 (-8.90–3.40), p=0.40
No differenceRoB: Some Concerns
The Effect of Heat Therapy on the Severity of Restless Legs Syndrome and Sleep Quality in the Elderly
Hojjat Azizkhani et al.. Complementary Medicine Journal 12(2) 202-213. (2022)
heat therapy
Quasi-ExperimentalN = 88
Severity of Restless Legs Syndrome— Mean difference 0.20, p=0.32
No differenceRoB: High
10.33588/rn.2909.99317
ropinirole
Quasi-ExperimentalN = 5
Sleep efficiency— Mean difference 20.2, p=0.01
Favors treatmentRoB: High
Effect of Intradialytic Resistance Exercise on Restless Legs Syndrome Among Hemodialysis Patients: A Pilot Randomized Controlled Trial
Achmad Fauzi et al.. Jurnal Keperawatan Komprehensif (Comprehensive Nursing Journal) 12(1) 1-8. (2026)
intradialytic resistance exercise
RCTN = 42
International RLS Severity Scale (IRLS) total score— Mean difference -0.60 (-2.30–1.10), p=0.52
No differenceRoB: Some Concerns
The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients
Hyoeun Bae et al.. Frontiers in Neurology 12 786408. (2021)
pregabalin
Quasi-Experimental
International Restless Legs Scale (IRLS) score— Mean difference -5.57, p=0.00
MixedRoB: High
Transcutaneous Spinal Cord Direct-Current Stimulation Modulates Functional Activity and Integration in Idiopathic Restless Legs Syndrome
Min Zeng et al.. Frontiers in Neuroscience 14 873. (2020)
transcutaneous spinal cord direct-current stimulation (tsdcs)
RCTN = 30
International RLS Rating Scale (IRLS-RS)— Mean difference -8.40
InconclusiveRoB: High
Aromatherapy Massage vs. Foot Reflexology on the Severity of Restless Legs Syndrome in Female Patients Undergoing Hemodialysis
Mahbobeh Ghasemi et al.. Geriatrics 6(4) 99. (2021)
aromatherapy massage
RCTN = 105
Severity of Restless Legs Syndrome— Mean difference -2.71, p=0.01
Favors treatmentRoB: Some Concerns
The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT
Susanne Macher et al.. Nutrients 12(5) 1313. (2020)
iron
RCTN = 176
Restless Legs Syndrome diagnosis (prevalence)
No differenceRoB: Some Concerns
Botulinum Toxin in Restless Legs Syndrome—A Randomized Double-Blind Placebo-Controlled Crossover Study
Shivam Om Mittal et al.. Toxins 10(10) 401. (2018)
incobotulinumtoxin a
CrossoverN = 24
International Restless Legs Syndrome Score (IRLS) — categorical improvement from severe to mild/moderate
Favors treatmentRoB: Some Concerns
Comparison of the effects of pramipexole and gabapentin on the treatment of restless leg syndrome in end-stage chronic renal failure patients undergoing hemodialysis
Sepideh Hajian et al.. Journal of Nephropathology 9(3) e25-e25. (2020)
pramipexole
RCTN = 60
RLS severity score (IRLSSG)— Mean difference 0.10
Favors treatmentRoB: High
Pengaruh Latihan Peregangan Intradialitik terhadap Restless Legs Syndrome pada Pasien Hemodialisis
Rogayah et al.. Jurnal Antara Keperawatan 482-486. (2022)
intradialytic stretching exercise
Quasi-ExperimentalN = 40
RLS symptom severity (IRLSSG score)— Mean difference -6.30
InconclusiveRoB: High
El efecto de la relajación muscular progresiva en la reducción del síndrome de las piernas inquietas entre los pacientes sometidos a hemodiálisis en una unidad periférica en Indonesia
Tria Firza Kumala et al.. Enfermería Nefrológica 24(4) 409-415. (2021)
progressive muscle relaxation
Quasi-ExperimentalN = 24
Restless Legs Syndrome severity score— Mean difference -6.08
Favors treatmentRoB: High
Comparison of the Effect of Reflexology and Swedish Massage on Restless Legs Syndrome and Sleep Quality in Patients Undergoing Hemodialysis: a Randomized Clinical Trial
Ghanbari A. et al.. International Journal of Therapeutic Massage & Bodywork: Research, Education, & Practice 15(2) 1-13. (2022)
foot reflexology and swedish massage
RCTN = 90
Restless Leg Syndrome severity score— Mean difference -0.23, p=0.23
No differenceRoB: Some Concerns
Nutritional Supplements and its Effect on Quality of Life and Sleep
H.. American Medical Journal 2(2) 104-110. (2011)
vitamin b12 injections
Quasi-ExperimentalN = 34
Insomnia improvement (percentage of subjects improved)
InconclusiveRoB: High
Clinical Efficacy of Heel Vessel Catgut Embedding in the Treatment of Primary Restless Legs Syndrome
Hui Shi et al.. International Journal of Pharmacology 21(1) 131-137. (2025)
heel vessel catgut embedding
RCTN = 42
International Restless Legs Syndrome Scale (IRLS) score— Mean difference -0.33, p=0.05
No differenceRoB: High
Abnormal Sleep Delta Rhythm and Interregional Phase Synchrony in Patients with Restless Legs Syndrome and Their Reversal by Dopamine Agonist Treatment
Jeong Woo Choi et al.. Journal of Clinical Neurology 13(4) 340. (2017)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Severity Scale (IRLS) score— Mean difference -16.4, p=0.03
Favors treatmentRoB: High
Efficacy and Safety of Pregabalin for Restless Legs Syndrome in Korean Adults: A Randomized, Double-Blind, Placebo-Controlled Trial
Jun-Sang Sunwoo et al.. Journal of Clinical Neurology 21(4) 325. (2025)
pregabalin
RCTN = 78
International Restless Legs Scale (IRLS) score change from baseline— Mean difference 1.50, p=0.42
No differenceRoB: Some Concerns
Holter electrocargiogram recording of periodic limbs movements in uremic restless legs syndrome: Application for diagnosis and evaluation of drug effects
Hidemaro Sato et al.. Nihon Toseki Igakkai Zasshi 36(3) 207-215. (2003)
pergolide mesylate
Quasi-Experimental
PLM frequency (periodic limb movements per 30 minutes) — Holter ECG recording— Mean difference -25.4, p=0.05
No differenceRoB: High
Examination of clinical effectiveness of Pramipexole for restless legs syndrome in hemodialysis patients
Takeshi Wakikawa et al.. Nihon Toseki Igakkai Zasshi 44(12) 1155-1161. (2011)
pramipexole
Quasi-Experimental
International Restless Legs Syndrome Rating Scale (IRLS) total score— Mean difference -10.3, p=0.00
InconclusiveRoB: High
Ropinirole in the Treatment of Patients With Restless Legs Syndrome: A US-Based Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Richard K. Bogan et al.. Mayo Clinic Proceedings 81(1) 17-27. (2006)
ropinirole
RCTN = 381
International Restless Legs Scale (IRLS) total score— Mean difference -2.20 (-3.60–-0.70), p=0.00
Favors treatmentRoB: Some Concerns
Repetitive Transcranial Magnetic Stimulation for the Treatment of Restless Legs Syndrome
Yi-Cong Lin et al.. Chinese Medical Journal 128(13) 1728-1731. (2015)
repetitive transcranial magnetic stimulation (rtms)
Quasi-Experimental
International RLS Rating Scale (IRLS-RS)— Mean difference -12.7, p=0.00
InconclusiveRoB: High
A double-blind, randomized, controlled trial to compare the efficacy and tolerability of fixed doses of ropinirole, bupropion, and iron in treatment of restless legs syndrome (Willis–Ekbom disease)
Kirti Vishwakarma et al.. Annals of Indian Academy of Neurology 19(4) 472-477. (2016)
ropinirole
RCTN = 90
International Restless Legs Scale (IRLS) severity score
MixedRoB: Some Concerns
The effects of two methods of reflexology and stretching exercises on the severity of restless leg syndrome among hemodialysis patients
Nahid Shahgholian et al.. Iranian Journal of Nursing and Midwifery Research 21(3) 219. (2016)
reflexology and stretching exercises
RCTN = 90
Restless leg syndrome severity score— Mean difference -15.9, p=0.00
Favors treatmentRoB: Some Concerns
The Effect of the cool dialysate on the restless leg syndrome in hemodialysis patients: Randomized triple-blind clinical trial
Mostafa Rad et al.. Iranian Journal of Nursing and Midwifery Research 24(3) 200. (2019)
cool dialysate
RCTN = 63
RLS severity score— Mean difference 3.06, p=0.05
No differenceRoB: Some Concerns
A prospective, randomized, open-label study comparing the efficacy and safety of clonazepam versus nortriptyline on quality of life in 40+ years old women presenting with restless leg syndrome
Annil Mahajan et al.. Journal of Mid-life Health 9(3) 135. (2018)
clonazepam
RCTN = 120
Restless Legs Syndrome Quality of Life Score— Mean difference 0.23, p=0.94
No differenceRoB: High
Comparative efficacy and safety of clonazepam versus nortriptyline in restless leg syndrome among forty plus women: A prospective, open-label randomized study
Annil Mahajan et al.. Journal of Mid-life Health 10(4) 197. (2019)
clonazepam
RCTN = 120
International Restless Leg Syndrome Scale (IRLSS) total score— Mean difference -1.46, p=0.36
MixedRoB: High
Biotin Deficiency as a Target for Treating Restless Legs Syndrome in Chronic Dialysis Patients
Heidi Moretti. Journal of Nephrology & Therapeutics 02(06). (2012)
biotin
RCTN = 37
International Restless Legs Syndrome Study Group (IRLS) Rating Scale Score
No differenceRoB: High
Pramipexole versus dual release levodopa in restless legs syndrome: a double blind, randomised, cross-over trial
Bassetti CL et al.. Swiss Medical Weekly 141(4748) w13274. (2011)
pramipexole
CrossoverN = 67
Periodic Limb Movement Index (PLM index, PLMI)— Mean difference -3.80, p=0.00
Favors treatmentRoB: Some Concerns
Comparison of aerobic and strength training exercises for restless leg syndrome, sleep quality, and daytime sleepiness in patients with diabetes mellitus: a randomized clinical trial
Fizah Mahnoor Khan et al.. Advances in Rehabilitation 39(4) 67-81. (2025)
aerobic and resistance training
RCTN = 42
International Restless Legs Syndrome Rating Scale total score— Mean difference 5.00, p=0.23
No differenceRoB: Some Concerns
Comparison of lacosamide versus levodopa in the treatment of restless legs syndrome in hemodialysis patients
Muhammad Ameem et al.. Pakistan Postgraduate Medical Journal 34(04) 192-196. (2023)
lacosamide
—
Effects of Alternative Therapies on Pain, Anxiety, Quality of Sleep, Activities of Daily Livings (ADLS) And Quality of Life in Patients with Restless Legs Syndrome (RLS): A Randomized Controlled Trial
Antara Bishnu, Priyanka Sethi. Journal of Chemical Health Risks. (2025)
yoga and physiotherapy
RCTN = 42
Pain severity (Visual Analog Scale)— Mean difference -2.17, p=0.00
MixedRoB: High
Effect of stretching exercises versus thermotherapy on restless legs syndrome symptoms, pain, and quality of sleep among pregnant women
Abeer Hassan Shamekh et al.. International journal of health sciences 11204-11220. (2022)
stretching exercises
Quasi-ExperimentalN = 60
Total RLS Symptoms Severity Score— Mean difference -4.43, p=0.00
Favors treatmentRoB: High
Effectiveness of a Self‑Stretching Exercise Program on Restless Leg Symptoms in Patients with Type 2 Diabetes Mellitus: A Pre-Post Intervention Analysis
Nasir Mehmood et al.. Pakistan BioMedical Journal 40-45. (2026)
self-stretching exercise
Quasi-Experimental
RLS-DI Sum Score
InconclusiveRoB: High
The Effect of Wet Cupping Therapy on Patients' Symptom Level and Sleep Quality on Restless Leg Syndrome
Gülsüm Yurttutan et al.. Ankara Medical Journal 20(4) 904-916. (2020)
wet cupping therapy
Quasi-ExperimentalN = 16
RLS Severity Scale Total Score (HBSSS / IRLSSG Severity Scale)— Mean difference -3.25, p=0.60
No differenceRoB: High
Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms
Jonathan D. Charlesworth et al.. Journal of Clinical Sleep Medicine 19(7) 1199-1209. (2023)
noninvasive peroneal nerve stimulation
CrossoverN = 43
International RLS Study Group Rating Scale (IRLS) total score— Mean difference -4.50
Favors treatmentRoB: Some Concerns
Magnesium citrate monotherapy improves restless legs syndrome symptoms and multiple suggested immobilization test scores in an open-label pilot study
Sasikanth Gorantla et al.. Journal of Clinical Sleep Medicine 20(8) 1357-1361. (2024)
magnesium citrate
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLS)— Mean difference 6.67 (2.33–11.0), p=0.01
InconclusiveRoB: High
Effect of Sensory Stimuli on Restless Legs Syndrome: A Randomized Crossover Study
Anouk D. Rozeman et al.. Journal of Clinical Sleep Medicine 10(8) 893-896. (2014)
sensory stimulation
CrossoverN = 21
Leg discomfort - Visual Analogue Scale at baseline (start of SIT)
No differenceRoB: Some Concerns
Pramipexole Alters Thermoregulation in Restless Legs Syndrome
Aaro V. Salminen et al.. Journal of Clinical Sleep Medicine 10(12) 1325-1329. (2014)
pramipexole
CrossoverN = 29
Subjective discomfort during suggested immobilization test (SIT)— Mean difference 4.10, p=0.00
Favors treatmentRoB: High
Decreased Symptoms without Augmented Skin Blood Flow in Subjects with RLS/WED after Vibration Treatment
Ulrike H. Mitchell et al.. Journal of Clinical Sleep Medicine 12(7) 947-952. (2016)
whole body vibration
CrossoverN = 13
RLS symptom severity (IRLS)
Favors treatmentRoB: Some Concerns
Effects of a 12-week yoga versus a 12-week educational film intervention on symptoms of restless legs syndrome and related outcomes: an exploratory randomized controlled trial
Kim E. Innes et al.. Journal of Clinical Sleep Medicine 16(1) 107-119. (2020)
yoga
RCTN = 41
International RLS Study Group Scale (IRLS) total score— Mean difference -5.24, p=0.01
Favors treatmentRoB: Some Concerns
Noninvasive neuromodulation reduces symptoms of restless legs syndrome
Mark J. Buchfuhrer et al.. Journal of Clinical Sleep Medicine 17(8) 1685-1694. (2021)
noninvasive peripheral nerve stimulation
CrossoverN = 43
International RLS Study Group Rating Scale (IRLS) score— Mean difference -3.43, p=0.00
Favors treatmentRoB: Some Concerns
10.5665/sleep/31.9.1229
pramipexole
RCTN = 43
PLMS Index (periodic leg movements during sleep per hour of sleep)— Mean difference -36.8, p=0.00
Favors treatmentRoB: Some Concerns
Pregabalin Versus Pramipexole: Effects on Sleep Disturbance in Restless Legs Syndrome
Diego Garcia-Borreguero et al.. Sleep 37(4) 635-643. (2014)
pregabalin
CrossoverN = 85
Wake After Sleep Onset (WASO) by polysomnography— Mean difference -27.1 (-35.8–-18.4), p=0.00
Favors treatmentRoB: Some Concerns
Clinical features of idiopathic restless legs syndrome in Japanese patients
Akito Kume et al.. Rinsho Shinkeigaku 50(6) 385-392. (2010)
dopaminergic agents
Quasi-Experimental
Response to dopaminergic treatment (improvement)
InconclusiveRoB: High
The Effect of Stretching Exercises on Severity of Restless Legs Syndrome in Patients on Hemodialysis
Mansooreh Aliasgharpour et al.. Asian Journal of Sports Medicine 7(2) e31001. (2016)
stretching exercises
RCTN = 36
Severity of restless legs syndrome symptoms— Mean difference -0.06, p=0.97
No differenceRoB: High
Effect of Pramipexole on Headache Relief in Patients with Concomitant Migraine and Restless Legs Syndrome; A Randomized, Controlled, Clinical Trial
Shahram Rafie et al.. Jundishapur Journal of Natural Pharmaceutical Products 14(3). (2019)
pramipexole
RCTN = 30
MIDAS Score (Migraine Disability Assessment Score)— Mean difference -1.46, p=0.09
No differenceRoB: Some Concerns
Effectiveness Of Buerger Allen Exercise Among Pregnant Women With Restless Leg Syndrome In A Selected Hospital Banke, Nepal
Srijana Sapkota. DIROSAT: Journal of Education, Social Sciences & Humanities 1(4) 159-166. (2023)
buerger allen exercise
Quasi-ExperimentalN = 60
RLS severity rating score— Mean difference -4.03
Favors treatmentRoB: High
Saint John's wort, an herbal inducer of the cytochrome P4503A4 isoform, may alleviate symptoms of Willis-Ekbom's disease
José Carlos Pereira et al.. Clinics 68(4) 469-474. (2013)
saint john's wort
Quasi-Experimental
Willis-Ekbom Disease severity score (IRLSSG rating scale)
Favors treatmentRoB: High
Investigating The Effect of Transcutaneous Electrical Nerve Stimulation on The Severity of Restless Legs Syndrome in Hemodialysis Patients
Abolfazl Kalmishi et al.. Scientific Journal of Kurdistan University of Medical Sciences 29(4) 49-58. (2024)
transcutaneous electrical nerve stimulation (tens)
RCTN = 60
Restless legs syndrome severity— Mean difference -0.37, p=0.69
No differenceRoB: High
Treatment of Willis-Ekbom Disease (Restless Leg Syndrome); The Efficacy of Mulligan's Traction Straight Leg Raise among Paramedical Professionals.
Usman Iqbal Janjua et al.. Journal of Health and Rehabilitation Research 3(2) 1052-1057. (2023)
mulligan's traction straight leg raise
RCTN = 38
RLS Rating Scale— Mean difference -0.90, p=0.56
No differenceRoB: High
Effects of Stretching Exercises and Myofascial Pain Release on Pain and Sleep Quality in Antenatal Restless Leg Syndrome
Hafiza Iqra Rubab et al.. Journal of Health and Rehabilitation Research 4(2) 194-199. (2024)
stretching exercises
RCTN = 22
Numeric Pain Rating Scale (NPRS)
InconclusiveRoB: High
Efficacy Of Interval Aerobic Training Versus Laser Puncture Therapy On The Severity Of Restless Leg Syndrome In Chronic Obstructive Lung Patients
Ola Mohamed Elgohary, Elgohary. International Journal of Environmental Sciences 6578-6588. (2025)
interval aerobic training
RCTN = 60
Restless Legs Syndrome Rating Scale (IRLS)— Mean difference -2.27, p=0.03
Favors treatmentRoB: High
Cortical spectral rebalancing underlies pregabalin’s efficacy in restless legs syndrome
Aref Zabeh et al.. bioRxiv (Cold Spring Harbor Laboratory). (2025)
pregabalin
RCTN = 103
RLS severity score (IRLSSG rating scale) — absolute score at baseline
Favors treatmentRoB: Some Concerns
Effektivitas aerobic exercise dan stretching exercise intradialytic terhadap penurunan restless leg syndrome pada pasien gagal ginjal kronik dengan hemodialisis
Achmad Fauzi et al.. Jurnal Keperawatan PPNI Jawa Barat 1(1). (2023)
aerobic exercise and stretching exercise
Quasi-ExperimentalN = 80
Restless Legs Syndrome severity level (categorical score)— Mean difference -0.63
Favors treatmentRoB: High
The Study on Effect of Korean Medical Treatment for Patients with Restless Legs Syndrome
Yu-Jin Lee et al.. Journal of Oriental Neuropsychiatry 26(4) 357-364. (2015)
korean medicine (herbal medication, acupuncture, oriental psychotherapy)
Quasi-Experimental
International Restless Legs Syndrome Study Group Rating Scale (IRLS)— Mean difference -5.08, p=0.06
No differenceRoB: High
Targeted Pressure on Abductor Hallucis and Flexor Hallucis Brevis Muscles to Manage Moderate to Severe Primary Restless Legs Syndrome
Phyllis J. Kuhn et al.. Journal of Osteopathic Medicine 116(7) 440-450. (2016)
targeted pressure device (abductor hallucis and flexor hallucis brevis muscles)
Quasi-Experimental
IRLSSG Rating Scale total score— Mean difference 5.22, p=0.00
InconclusiveRoB: High
| Reference | Primary outcome & effect | Result | RoB | |||
|---|---|---|---|---|---|---|
| 10.1002/1531-8257(199901)14/1<138//aid-mds1023>3.0.co;2-a | ropinirole | Quasi-Experimental | — | IRLSSG abbreviated questionnaire score Mean difference -10.9, p=0.00 | Favors treatment | High |
| 10.1002/1531-8257(200003)15/2<324//aid-mds1020>3.0.co;2-4 | amantadine | Quasi-Experimental | — | RLS rating scale score Mean difference -3.20, p=0.00 | Inconclusive | High |
| A randomized double‐blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia Vanessa Short et al.. American Journal of Hematology 99(6) 1077-1083. (2024) | iron | RCT | 100 | Change from baseline in IRLSS score at Week 6 | No difference | Some Concerns |
| Dissociation of periodic leg movements from arousals in restless legs syndrome Mauro Manconi et al.. Annals of Neurology 71(6) 834-844. (2012) | pramipexole | RCT | 46 | PLMS index (entire night) - periodic leg movements during sleep per hour | Inconclusive | Some Concerns |
| A double‐blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome Arthur S. Walters et al.. Annals of Neurology 24(3) 455-458. (1988) | bromocriptine | Crossover | 6 | Periodic movements of sleep per hour of sleep Mean difference -49.0, p=0.03 | Favors treatment | Some Concerns |
| Effects of Different Exercise Programs on Symptoms, Sleep, and Quality of Life in Patients with Primary Restless Legs Syndrome Özge Çoban et al.. Movement Disorders Clinical Practice 10(9) 1349-1359. (2023) | aerobic exercise and stretching exercise | RCT | 24 | RLS Symptom Severity Mean difference 6.33, p=0.02 | Favors treatment | Some Concerns |
| One‐year treatment with standard and sustained‐release levodopa: Appropriate long‐term treatment of restless legs syndrome? Claudia Trenkwalder et al.. Movement Disorders 18(10) 1184-1189. (2003) | levodopa/benserazide | Quasi-Experimental | — | Satisfaction with sleep Mean difference 3.50, p=0.00 | Favors treatment | High |
| Treatment of restless legs syndrome with the dopamine agonist alpha‐dihydroergocryptine Frithjof Tergau et al.. Movement Disorders 16(4) 731-735. (2001) | alpha-dihydroergocryptine | Quasi-Experimental | — | Overall complaints (daytime) — VAS Mean difference -18.0, p=0.00 | Inconclusive | High |
| Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome: A double‐blind, placebo‐controlled pilot study Stiasny-Kolster K. et al.. Movement Disorders 19(12) 1432-1438. (2004) | rotigotine | RCT | 63 | International Restless Legs Syndrome Scale (IRLS) total score Mean difference 2.50 (-3.50–8.40), p=0.41 | No difference | Some Concerns |
| Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: A 12‐week, double‐blind, randomized, parallel‐group, placebo‐controlled study Arthur S. Walters et al.. Movement Disorders 19(12) 1414-1423. (2004) | ropinirole | RCT | 267 | Change from baseline in International Restless Legs Scale (IRLS) score at week 12 Mean difference -2.50 (-4.60–-0.40), p=0.02 | Favors treatment | Low |
| Validation of the “L‐DOPA test” for diagnosis of restless legs syndrome Karin Stiasny‐Kolster et al.. Movement Disorders 21(9) 1333-1339. (2006) | levodopa/benserazide | Quasi-Experimental | — | Severity of symptoms in the legs (L-DOPA test) — change from baseline Mean difference -52.2 | Inconclusive | High |
| Controlled withdrawal of pramipexole after 6 months of open‐label treatment in patients with restless legs syndrome Claudia Trenkwalder et al.. Movement Disorders 21(9) 1404-1410. (2006) | pramipexole | RCT | 150 | Time to target event (insufficient therapeutic response) | Favors treatment | Some Concerns |
| Ropinirole is effective in the long‐term management of restless legs syndrome: A randomized controlled trial Jacques Montplaisir et al.. Movement Disorders 21(10) 1627-1635. (2006) | ropinirole | RCT | 92 | Proportion of patients relapsing during double-blind treatment phase Odds ratio 0.33 (0.13–0.81), p=0.02 | Favors treatment | Some Concerns |
| Efficacy of pramipexole in restless legs syndrome: A six‐week, multicenter, randomized, double‐blind study (effect‐RLS study) Wolfgang H. Oertel et al.. Movement Disorders 22(2) 213-219. (2007) | pramipexole | RCT | 345 | International RLS Study Group Rating Scale (IRLS) score Mean difference -6.60 (-8.60–-4.50), p=0.00 | Favors treatment | Some Concerns |
| Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: Results from a multi‐center, randomized, active controlled trial Claudia Trenkwalder et al.. Movement Disorders 22(5) 696-703. (2007) | cabergoline | RCT | 361 | IRLS total score change from baseline to Week 6/8 (short-term primary endpoint) Mean difference -6.60 (-8.60–-4.70), p=0.00 | Favors treatment | Some Concerns |
| Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome Vincenzo Rizzo et al.. Movement Disorders 24(5) 710-715. (2009) | dopaminergic agents | Quasi-Experimental | — | Motor-evoked potential (MEP) amplitude after paired associative stimulation | Inconclusive | High |
| A randomized, double‐blind, placebo controlled, multi‐center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome Ludger Grote et al.. Movement Disorders 24(10) 1445-1452. (2009) | iron | RCT | 60 | International Restless Legs Syndrome Study Group Rating Scale (IRLS) score at week 11 Mean difference -6.30, p=0.02 | No difference | Some Concerns |
| Rotigotine improves restless legs syndrome: A 6‐month randomized, double‐blind, placebo‐controlled trial in the United States Wayne A. Hening et al.. Movement Disorders 25(11) 1675-1683. (2010) | rotigotine | RCT | 505 | IRLS sum score Mean difference -2.20 (-4.50–0.20), p=0.07 | No difference | Some Concerns |
| Pramipexole versus ropinirole: Polysomnographic acute effects in restless legs syndrome Mauro Manconi et al.. Movement Disorders 26(5) 892-895. (2011) | pramipexole and ropinirole | Quasi-Experimental | — | Median survival time | Inconclusive | High |
| Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome John W. Winkelman et al.. Movement Disorders 26(11) 2065-2072. (2011) | gabapentin enacarbil | Crossover | 136 | Wake time during sleep (WTDS) Mean difference -26.0 (-35.6–-16.4), p=0.00 | Favors treatment | Some Concerns |
| Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis‐Ekbom Disease): Results from a prospective, multicenter study over 66 weeks Diego García‐Borreguero et al.. Movement Disorders 27(2) 277-283. (2012) | ropinirole | RCT | 404 | Change from baseline in IRLS total score at week 12 (primary endpoint) Mean difference -2.10 (-4.00–-0.10), p=0.04 | Mixed | Some Concerns |
| Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial Claudia Trenkwalder et al.. Movement Disorders 32(10) 1478-1482. (2017) | iron | RCT | 110 | International Restless Legs Syndrome Severity Scale (IRLS) total score Mean difference -2.90 (-5.93–1.02), p=0.16 | No difference | Some Concerns |
| Increased Blood Pressure Dipping in Restless Legs Syndrome With Rotigotine: A Randomized Trial Sofiene Chenini et al.. Movement Disorders 35(12) 2164-2173. (2020) | rotigotine | RCT | 70 | Percentage of systolic BP nondippers at end point Odds ratio 2.92 (1.08–7.89), p=0.03 | Favors treatment | Low |
| A Randomized, Placebo‐Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome Diego Garcia‐Borreguero et al.. Movement Disorders 36(10) 2387-2392. (2021) | dipyridamole | Crossover | 28 | International Restless Legs Rating Scale (IRLS) Mean difference -8.00, p=0.00 | Favors treatment | Low |
| Treatment of restless leg syndrome with pergolide—an open clinical trial Juliane Winkelmann et al.. Movement Disorders 13(3) 566-569. (1998) | pergolide | Quasi-Experimental | — | RLS symptom severity classification (categorical: no/mild/severe RLS) | Inconclusive | High |
| Evaluation of periodic leg movements and associated transcranial magnetic stimulation parameters in restless legs syndrome Yasar Kutukcu et al.. Muscle & Nerve 33(1) 133-137. (2006) | dopaminergic agents | Quasi-Experimental | — | Cortical Silent Period (CSP) duration - Right Tibialis Anterior Mean difference -31.2, p=0.01 | Inconclusive | High |
| Carbamazepine in restless legs Lundvall O. et al.. European Journal of Clinical Pharmacology 25(3) 323-324. (1983) | carbamazepine | Crossover | 6 | Number of days with sensations of restless legs per week | Inconclusive | High |
| Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa Staedt J. et al.. Journal of Neural Transmission 104(4-5) 461-468. (1997) | pergolide | Crossover | 11 | NMS cluster disturbed time Mean difference -74.0, p=0.03 | Favors treatment | Some Concerns |
| Restless legs syndrome is a relevant comorbidity in patients with inflammatory bowel disease Janek Becker et al.. International Journal of Colorectal Disease 33(7) 955-962. (2018) | iron | Quasi-Experimental | — | International RLS Severity Scale (IRLS) score — iron supplementation group | Inconclusive | High |
| Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome Saletu M. et al.. European Archives of Psychiatry and Clinical Neuroscience 252(4) 185-194. (2002) | pramipexole | Crossover | 11 | PLM index per hour of sleep (PLM/h TST) Mean difference -26.8, p=0.03 | Favors treatment | High |
| Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid Ilonka Eisensehr et al.. Journal of Neurology 251(5) 579-583. (2004) | levodopa/benserazide | Crossover | 20 | RLS symptom intensity score Mean difference -1.70, p=0.02 | Mixed | Some Concerns |
| Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study Birgit Högl et al.. Journal of Neurology 257(2) 230-237. (2010) | levodopa | Quasi-Experimental | — | Augmentation occurrence (expert consensus diagnosis) | Inconclusive | High |
| Impairment of sensory-motor integration in patients affected by RLS Rizzo V. et al.. Journal of Neurology 257(12) 1979-1985. (2010) | dopaminergic agents | Quasi-Experimental | — | International RLS Rating Scale (IRLS-RS) | Favors treatment | High |
| Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS patients: a multicentre, randomized, placebo-controlled study Benes H. et al.. Journal of Neurology 258(6) 1046-1054. (2011) | ropinirole | RCT | 266 | Montgomery-Asberg Depression Rating Scale (MADRS) total score Mean difference -3.60 (-5.60–-1.60), p=0.00 | Favors treatment | Some Concerns |
| Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa and sr-L-dopa in restless legs syndrome Saletu M. et al.. Journal of Neural Transmission 110(6) 611-626. (2003) | levodopa/benserazide | Crossover | 21 | PLM index per hour of sleep (PLM/h TST) Mean difference -15.5, p=0.00 | Favors treatment | Some Concerns |
| Computerized movement analysis and beta-CIT-SPECT in patients with restless legs syndrome Mrowka M. et al.. Journal of Neural Transmission 112(5) 693-701. (2005) | levodopa | Crossover | — | Movement frequency (FREQ) - alternating forearm pronation/supination, hand tapping, finger tapping, hip flexion/extension before and after L-dopa | Inconclusive | High |
| Lisuride treatment of Restless Legs Syndrome: first studies with monotherapy in de novo patients and in combination with levodopa in advanced disease Benes H. et al.. Journal of Neural Transmission 113(1) 87-92. (2006) | lisuride | Quasi-Experimental | — | PLM Index per hour (PLM/h during time in bed) | Inconclusive | High |
| Comparative placebo-controlled polysomnographic and psychometric studies on the acute effects of gabapentin versus ropinirole in restless legs syndrome Michael Saletu et al.. Journal of Neural Transmission 117(4) 463-473. (2010) | gabapentin | RCT | 80 | Sleep Efficiency Index Mean difference 6.90, p=0.01 | Favors treatment | Some Concerns |
| Postural control in restless legs syndrome with medication intervention using pramipexole Aulikki Ahlgrén-Rimpiläinen et al.. Neurological Sciences 35(2) 199-204. (2014) | pramipexole | Quasi-Experimental | — | Center point of force velocity eyes open (CPFV EO) Mean difference -0.31, p=0.01 | No difference | High |
| Repetitive transcranial magnetic stimulation in restless legs syndrome: preliminary results Burcu Altunrende et al.. Neurological Sciences 35(7) 1083-1088. (2014) | repetitive transcranial magnetic stimulation (rtms) | RCT | 19 | International RLS Rating Scale score Mean difference 2.10, p=0.21 | No difference | High |
| The effect of vitamin D supplements on the severity of restless legs syndrome Siraj Wali et al.. Sleep and Breathing 19(2) 579-583. (2015) | vitamin d3 | Quasi-Experimental | — | RLS severity score Mean difference -16.0, p=0.00 | Inconclusive | High |
| Effects of sleep hygiene training given to pregnant women with restless leg syndrome on their sleep quality Ayşe Sönmez et al.. Sleep and Breathing 22(2) 527-535. (2018) | sleep hygiene training | Quasi-Experimental | 128 | PSQI Total Score Mean difference -0.39, p=0.35 | No difference | High |
| Efficacy of vitamin D replacement therapy in restless legs syndrome: a randomized control trial Wali SO et al.. Sleep and Breathing 23(2) 595-601. (2019) | vitamin d | RCT | 35 | IRLSSG rating scale score (RLS severity score) — all participants Mean difference 4.20 (-12.8–4.40), p=0.32 | No difference | Some Concerns |
| Effects of Bariatric Surgery on Sleep Disorder Symptoms and Sleep Quality Vahit Mutlu et al.. Obesity Surgery 35(12) 5471-5479. (2025) | bariatric surgery | Quasi-Experimental | — | Restless Legs Syndrome Severity Scale (IRLSSG) Mean difference -3.04, p=0.00 | Favors treatment | High |
| 10.1007/s12311-012-0382-6 | lisuride | Quasi-Experimental | — | PLMs index (periodic leg movements per hour of sleep) Mean difference -21.5, p=0.02 | Inconclusive | High |
| Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects Willi Cawello et al.. Clinical Drug Investigation 34(2) 95-105. (2014) | rotigotine (neupro) | Quasi-Experimental | — | AUClast of unconjugated rotigotine Rate ratio 1.10 | Inconclusive | High |
| Sleep and Quality of Life Under Prolonged Release Oxycodone/Naloxone for Severe Restless Legs Syndrome: An Analysis of Secondary Efficacy Variables of a Double-Blind, Randomized, Placebo-Controlled Study with an Open-Label Extension Wolfgang H. Oertel et al.. CNS Drugs 30(8) 749-760. (2016) | oxycodone/naloxone | RCT | 304 | MOS Sleep Scale - Sleep Disturbance Domain Mean difference -18.6 (-24.4–-12.9), p=0.00 | Favors treatment | Low |
| Treatment of Sleep, Motor and Sensory Symptoms with the Orexin Antagonist Suvorexant in Adults with Idiopathic Restless Legs Syndrome: A Randomized Double-Blind Crossover Proof-of-Concept Study Diego Garcia-Borreguero et al.. CNS Drugs 38(1) 45-54. (2024) | suvorexant | Crossover | 41 | Wake After Sleep Onset (WASO) Mean difference -46.5, p=0.00 | Favors treatment | Some Concerns |
| Acupressure reduces the severity of restless legs syndrome in hemodialysis patients: A cluster-randomized crossover pilot study Li-Hung Tsai et al.. Biomedical Journal 45(3) 533-541. (2022) | acupressure | Crossover | 27 | RLS severity (International Restless Legs Syndrome Rating Scale) Mean difference 3.70 (1.62–5.78), p=0.00 | Favors treatment | High |
| Effects of Transcutaneous Spinal Direct Current Stimulation in Idiopathic Restless Legs Patients Heide AC et al.. Brain Stimulation 7(5) 636-642. (2014) | transcutaneous spinal direct current stimulation (tsdcs) | Crossover | 20 | RLS symptom severity - Visual Analogue Scale Mean difference -28.8, p=0.00 | Favors treatment | Some Concerns |
| Relationship of periodic leg movements and severity of restless legs syndrome: A study in unmedicated and medicated patients Magdolna Hornyak et al.. Clinical Neurophysiology 118(7) 1532-1537. (2007) | pergolide | RCT | 100 | International RLS Study Group Rating Scale (IRLS) total score Mean difference -10.4 | Favors treatment | Some Concerns |
| Cutaneous silent period in patients with restless leg syndrome Jin-Kyu Han et al.. Clinical Neurophysiology 118(8) 1705-1710. (2007) | dopaminergic agents | Quasi-Experimental | — | Cutaneous Silent Period (CSP) Duration Mean difference 8.99, p=0.00 | Favors treatment | High |
| Effect of pramipexole on cutaneous-silent-period parameters in patients with restless legs syndrome Oğuzhan Öz et al.. Clinical Neurophysiology 123(1) 154-159. (2012) | pramipexole | Quasi-Experimental | — | Cutaneous silent period latency - upper extremity (UE CSP latency) Mean difference -0.10, p=0.96 | No difference | High |
| Evaluation of Gabapentin Enacarbil on Cardiac Repolarization: A Randomized, Double-Blind, Placebo- and Active-Controlled, Crossover Thorough QT/QTc Study in Healthy Adults Dan Chen et al.. Clinical Therapeutics 34(2) 351-362.e3. (2012) | gabapentin enacarbil | Crossover | 54 | Time-matched difference in baseline-adjusted QTcIb (ddQTcIb) — gabapentin enacarbil 1200 mg vs placebo Mean difference -0.30 | Favors treatment | Low |
| Short-term effects of massage with olive oil on the severity of uremic restless legs syndrome: A double-blind placebo-controlled trial Morteza Nasiri et al.. Complementary Therapies in Medicine 44 261-268. (2019) | massage with olive oil | RCT | 60 | Total IRLSSG Rating Scale score (RLS severity) Mean difference -1.55, p=0.36 | No difference | Some Concerns |
| Thermo-therapy and cryotherapy to decrease the symptoms of restless leg syndrome during the pregnancy: A randomized clinical trial Hadi Jafarimanesh et al.. Complementary Therapies in Medicine 50 102409. (2020) | cold water immersion | RCT | 80 | Restless Legs Syndrome symptom severity Mean difference -2.48, p=0.02 | Favors treatment | Some Concerns |
| Neurocognitive function in patients with idiopathic Restless Legs Syndrome before and after treatment with dopamine-agonist Andrea Galbiati et al.. International Journal of Psychophysiology 95(3) 304-309. (2015) | pramipexole | Quasi-Experimental | — | Total Sleep Time (TST) Mean difference 87.2, p=0.00 | Favors treatment | High |
| Treatment of Restless Legs Syndrome Improves Agitation and Sleep in Persons with Dementia: A Randomized Trial Kathy C. Richards et al.. Journal of the American Medical Directors Association 26(5) 105485. (2025) | gabapentin enacarbil | RCT | 147 | Nighttime agitation (5 PM to 7 AM) - CMAI Index Mean difference -1.67, p=0.00 | Favors treatment | Some Concerns |
| Evaluation of Acupuncture in the Treatment of Restless Legs Syndrome: A Randomized Controlled Trial Gholam Reza Raissi et al.. Journal of Acupuncture and Meridian Studies 10(5) 346-350. (2017) | acupuncture plus gabapentin | RCT | 50 | International Restless Legs Syndrome Study Group Rating Scale (IRLSRS) Mean difference -2.30 | Favors treatment | Some Concerns |
| Effects of glycerin oil and lavender oil massages on hemodialysis patients’ restless legs syndrome Neda Mirbagher Ajorpaz et al.. Journal of Bodywork and Movement Therapies 24(1) 88-92. (2020) | lavender oil and glycerin oil massage | RCT | 105 | Restless Legs Syndrome severity score Mean difference -14.4, p=0.02 | Favors treatment | Some Concerns |
| Long-term open-label study of pramipexole in patients with primary restless legs syndrome Yuichi Inoue et al.. Journal of the Neurological Sciences 294(1-2) 62-66. (2010) | pramipexole | Quasi-Experimental | 141 | International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score | Inconclusive | High |
| Whole body and local cryotherapy in restless legs syndrome: A randomized, single-blind, controlled parallel group pilot study Svenja Happe et al.. Journal of the Neurological Sciences 370 7-12. (2016) | cryotherapy | RCT | 43 | International RLS Severity Scale (IRLS) score Mean difference -6.10 | Favors treatment | Some Concerns |
| Feasibility and efficacy of a physical activity intervention for managing restless legs syndrome in multiple sclerosis: Results of a pilot randomized controlled trial Katie L.J Cederberg et al.. Multiple Sclerosis and Related Disorders 50 102836. (2021) | physical activity intervention | RCT | 15 | Overall RLS Severity (IRLS Total Score) Mean difference -7.90, p=0.01 | Favors treatment | High |
| Use of gabapentin for attenuation of symptoms following rapid opiate detoxification (ROD) Freye E. et al.. Neurophysiologie Clinique/Clinical Neurophysiology 34(2) 81-89. (2004) | gabapentin | Quasi-Experimental | — | Amplitude of late N100-peak of somatosensory evoked potential (SEP) Mean difference 3.90, p=0.01 | Inconclusive | High |
| Noninvasive Vagus Nerve Stimulation: A New Therapeutic Approach for Pharmacoresistant Restless Legs Syndrome Sarah Hartley et al.. Neuromodulation: Technology at the Neural Interface 26(3) 629-637. (2023) | transauricular vagus nerve stimulation (tvns) | Quasi-Experimental | — | Restless Legs Syndrome severity (IRLS score) Mean difference -7.30, p=0.00 | Favors treatment | High |
| Hyperalgesia and functional sensory loss in restless legs syndrome Karin Stiasny-Kolster et al.. Pain 154(8) 1457-1463. (2013) | levodopa | Quasi-Experimental | — | IRLS Severity Scale (International RLS Study Group Severity Scale) Mean difference -5.20, p=0.05 | No difference | High |
| Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome Hideto Shinno et al.. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34(3) 522-526. (2010) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLS) Mean difference -7.20, p=0.00 | Favors treatment | High |
| Long-term efficacy and safety of gabapentin enacarbil in Japanese restless legs syndrome patients Yuichi Inoue et al.. Progress in Neuro-Psychopharmacology and Biological Psychiatry 36(2) 251-257. (2012) | gabapentin enacarbil | Quasi-Experimental | — | International Restless Legs Syndrome Scale (IRLS) total score | Inconclusive | High |
| Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome Yuichi Inoue et al.. Progress in Neuro-Psychopharmacology and Biological Psychiatry 40(1) 326-333. (2013) | rotigotine | Quasi-Experimental | — | IRLSSG Rating Scale (IRLS) total score | Inconclusive | High |
| Circadian effects of dopaminergic treatment in restless legs syndrome Diego Garcia-Borreguero et al.. Sleep Medicine 5(4) 413-420. (2004) | levodopa/carbidopa | Quasi-Experimental | — | Dim Light Melatonin Onset (DLMO) Mean difference -2.17, p=0.05 | No difference | High |
| The treatment of restless legs syndrome with intravenous iron dextran Christopher J. Earley et al.. Sleep Medicine 5(3) 231-235. (2004) | iron | Quasi-Experimental | — | Global Rating Scale (GRS) score for RLS severity - percent decrease at 2 weeks | Inconclusive | High |
| Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome Bliwise DL et al.. Sleep Medicine 6(2) 141-147. (2005) | ropinirole | RCT | 26 | NREM Periodic Leg Movements in Sleep Index (PLMSI) Mean difference -56.6, p=0.01 | Favors treatment | Some Concerns |
| Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome Earley CJ et al.. Sleep Medicine 6(4) 301-305. (2005) | iron | Quasi-Experimental | — | Global RLS Rating Scale | Inconclusive | High |
| Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome Benes H.. Sleep Medicine 7(1) 31-35. (2006) | lisuride | RCT | 9 | International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score Mean difference -12.9 | Favors treatment | High |
| Efficacy and safety of pramipexole in idiopathic restless legs syndrome: A polysomnographic dose-finding study—The PRELUDE study Markku Partinen et al.. Sleep Medicine 7(5) 407-417. (2006) | pramipexole | RCT | 109 | Periodic Limb Movements during Time in Bed Index (PLMI) | Favors treatment | Some Concerns |
| Efficacy and tolerability of sumanirole in restless legs syndrome: A phase II, randomized, double-blind, placebo-controlled, dose–response study Diego Garcia-Borreguero et al.. Sleep Medicine 8(2) 119-127. (2007) | sumanirole | RCT | 270 | IRLS-10 total score change from baseline to end of maintenance Mean difference -0.14 | No difference | Some Concerns |
| A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome Diego Garcia-Borreguero et al.. Sleep Medicine 8(7-8) 742-752. (2007) | ropinirole | Quasi-Experimental | — | IRLS total score | Inconclusive | High |
| First night efficacy of pramipexole in restless legs syndrome and periodic leg movements Mauro Manconi et al.. Sleep Medicine 8(5) 491-497. (2007) | pramipexole | RCT | 32 | PLMS Change Index (normalized change in PLMS index from baseline to treatment night) | Favors treatment | Some Concerns |
| Efficacy of rotigotine transdermal system in severe restless legs syndrome: A randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe Wolfgang H. Oertel et al.. Sleep Medicine 9(3) 228-239. (2008) | rotigotine | RCT | 341 | IRLS total score change from baseline to end of Maintenance Period Mean difference -1.30 (-5.00–2.30), p=0.23 | No difference | Some Concerns |
| Clinical efficacy of ropinirole for restless legs syndrome is not affected by age at symptom onset Richard P. Allen et al.. Sleep Medicine 9(8) 899-902. (2008) | ropinirole | RCT | 996 | Change from baseline in IRLS total score at Week 12 LOCF | Favors treatment | Some Concerns |
| Open-label study of the long-term efficacy and safety of pramipexole in patients with Restless Legs Syndrome (extension of the PRELUDE study) Markku Partinen et al.. Sleep Medicine 9(5) 537-541. (2008) | pramipexole | Quasi-Experimental | — | International RLS Study Group Rating Scale (IRLS) | Inconclusive | High |
| One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome Wolfgang H. Oertel et al.. Sleep Medicine 9(8) 865-873. (2008) | rotigotine | Quasi-Experimental | — | IRLS total score | Inconclusive | High |
| A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: Polysomnographic evaluation of periodic leg movements and sleep disturbance Leni Jama et al.. Sleep Medicine 10(6) 630-636. (2009) | pramipexole | RCT | 109 | Periodic limb movements during time in bed index (PLMI) | Favors treatment | Some Concerns |
| Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial Ferini-Strambi L. et al.. Sleep Medicine 9(8) 874-881. (2008) | pramipexole | RCT | 369 | International RLS Study Group Rating Scale (IRLS) total score Mean difference -3.80, p=0.00 | Favors treatment | Low |
| Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study James Wang et al.. Sleep Medicine 10(9) 973-975. (2009) | iron | RCT | 18 | International Restless Legs Scale (IRLS) score Mean difference -9.16, p=0.01 | Favors treatment | Some Concerns |
| Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized, double-blind, placebo-controlled study Yuichi Inoue et al.. Sleep Medicine 11(1) 11-16. (2010) | pramipexole | RCT | 41 | Periodic Limb Movements in Bed Index (PLMI) | Favors treatment | Some Concerns |
| Effects of melatonin and bright light administration on motor and sensory symptoms of RLS Whittom S. et al.. Sleep Medicine 11(4) 351-355. (2010) | bright light exposure | Crossover | 8 | SIT-PLM index (Suggested Immobilization Test - Periodic Leg Movements index) Mean difference 71.0, p=0.04 | Mixed | High |
| Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: A randomized, placebo-controlled polysomnographic study Wolfgang H. Oertel et al.. Sleep Medicine 11(9) 848-856. (2010) | rotigotine | RCT | 67 | Periodic Limb Movement Index (PLMI; PLM/h time in bed) Rate ratio 4.25 (2.48–7.28), p=0.00 | Favors treatment | Low |
| A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome Richard Allen et al.. Sleep Medicine 11(6) 512-519. (2010) | pregabalin | RCT | 137 | IRLS Total Score change from baseline Mean difference -4.10 | Favors treatment | Some Concerns |
| Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep Mauro Manconi et al.. Sleep Medicine 12(1) 47-55. (2011) | pramipexole | RCT | 23 | PLMS index (periodic leg movements during sleep per hour of sleep) Mean difference -29.9 | No difference | High |
| Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood Pasquale Montagna et al.. Sleep Medicine 12(1) 34-40. (2011) | pramipexole | RCT | 404 | IRLS total score change from baseline to week 12 Mean difference 6.10 (4.30–7.90), p=0.00 | Favors treatment | Low |
| Evaluation of painful sensory symptoms in restless legs syndrome: Experience from two clinical trials Magdolna Hornyak et al.. Sleep Medicine 12(2) 186-189. (2011) | pramipexole | RCT | — | RLS-related limb-pain VAS score — Trial 615 Mean difference -12.7, p=0.00 | Favors treatment | Some Concerns |
| Efficacy and augmentation during 6months of double-blind pramipexole for restless legs syndrome Birgit Högl et al.. Sleep Medicine 12(4) 351-360. (2011) | pramipexole | RCT | 331 | International RLS Study Group Rating Scale (IRLS) total score — change from baseline Mean difference -2.60, p=0.01 | Favors treatment | Some Concerns |
| l-Dopa improves Restless Legs Syndrome and periodic limb movements in sleep but not Attention-Deficit-Hyperactivity Disorder in a double-blind trial in children Sandra J. England et al.. Sleep Medicine 12(5) 471-477. (2011) | levodopa | Factorial | 37 | Parent Conners' Rating Scale — Oppositional T score | No difference | Some Concerns |
| Efficacy and safety of pramipexole in chinese patients with restless legs syndrome: Results from a multi-center, randomized, double-blind, placebo-controlled trial Jian-Fang Ma et al.. Sleep Medicine 13(1) 58-63. (2012) | pramipexole | RCT | 306 | Change from baseline to week 6 in IRLS total score Mean difference -4.52, p=0.00 | Favors treatment | Some Concerns |
| Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: A multi-centred, placebo-controlled preliminary clinical trial Richard P. Allen et al.. Sleep Medicine 12(9) 906-913. (2011) | iron | RCT | 46 | International Restless Legs Syndrome study group severity scale (IRLS) change from baseline Mean difference -0.90, p=0.61 | No difference | Some Concerns |
| Leg movements during wakefulness in restless legs syndrome: Time structure and relationships with periodic leg movements during sleep Raffaele Ferri et al.. Sleep Medicine 13(5) 529-535. (2012) | pramipexole | RCT | 35 | PLMW index (periodic leg movements during wakefulness per hour) Mean difference 12.7 | No difference | Some Concerns |
| Augmentation in the treatment of restless legs syndrome with transdermal rotigotine Heike Beneš et al.. Sleep Medicine 13(6) 589-597. (2012) | rotigotine | RCT | 962 | Clinically relevant augmentation (MPI criteria) Risk difference 0.01 | Favors treatment | Some Concerns |
| Efficacy of vitamins C, E, and their combination for treatment of restless legs syndrome in hemodialysis patients: A randomized, double-blind, placebo-controlled trial Mohammad Mahdi Sagheb et al.. Sleep Medicine 13(5) 542-545. (2012) | vitamins c and e | RCT | 60 | Absolute change in IRLS sum score from baseline to end of treatment Mean difference -7.20, p=0.00 | Favors treatment | Some Concerns |
| A phase II, open-label, non-comparative study of Botulinum toxin in Restless Legs Syndrome Imad Ghorayeb et al.. Sleep Medicine 13(10) 1313-1316. (2012) | botulinum toxin type a | Quasi-Experimental | 27 | Proportion of responders with >=50% improvement of IRLSRS score at week 2 | No difference | High |
| Lower molecular weight intravenous iron dextran for restless legs syndrome Yong Won Cho et al.. Sleep Medicine 14(3) 274-277. (2013) | iron | Quasi-Experimental | — | Korean version of the International RLS Severity Scale (K-IRLS) Mean difference -6.80, p=0.00 | Inconclusive | High |
| Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study Yuichi Inoue et al.. Sleep Medicine 14(11) 1085-1091. (2013) | rotigotine | RCT | 284 | International Restless Legs Syndrome Study Group rating scale (IRLS) total score Mean difference -2.80 (-5.30–-0.30), p=0.03 | Favors treatment | Some Concerns |
| Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study Jingyu Zhang et al.. Sleep Medicine 16(1) 181-185. (2015) | pramipexole | RCT | 204 | International RLS Study Group Rating Scale (IRLS) score Mean difference 3.80, p=0.00 | Favors treatment | Some Concerns |
| Sternberg working memory performance following treatment with pramipexole in patients with moderate-to-severe restless legs syndrome Ki-Young Jung et al.. Sleep Medicine 16(6) 703-708. (2015) | pramipexole | Quasi-Experimental | — | International RLS Severity Scale (IRLS) score Mean difference -16.1, p=0.00 | Favors treatment | High |
| Significant association between systolic and diastolic blood pressure elevations and periodic limb movements in patients with idiopathic restless legs syndrome Werner Cassel et al.. Sleep Medicine 17 109-120. (2016) | rotigotine | RCT | — | Number of PLM-associated elevations of systolic blood pressure (SBP) during the night | Inconclusive | Some Concerns |
| Mapping intrinsic functional brain changes and repetitive transcranial magnetic stimulation neuromodulation in idiopathic restless legs syndrome: a resting-state functional magnetic resonance imaging study Chunyan Liu et al.. Sleep Medicine 16(6) 785-791. (2015) | repetitive transcranial magnetic stimulation (rtms) | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLSSG) Mean difference -9.00, p=0.00 | Favors treatment | High |
| Daytime symptoms of restless legs syndrome – clinical characteristics and rotigotine effectiveness Masayoshi Takahashi et al.. Sleep Medicine 16(7) 871-876. (2015) | rotigotine | RCT | 284 | Change in duration of daytime RLS symptoms (minutes/day) Mean difference -54.4 (-102–-7.00), p=0.03 | Favors treatment | Some Concerns |
| Chronic dopaminergic treatment in restless legs syndrome: does it affect the autonomic nervous system? Camilla Rocchi et al.. Sleep Medicine 16(9) 1071-1076. (2015) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Study Group rating scale (IRLS) Mean difference -16.8, p=0.00 | Favors treatment | High |
| Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome Juliane Schneider et al.. Sleep Medicine 16(11) 1342-1347. (2015) | iron | Quasi-Experimental | — | International Restless Legs Syndrome Study Group rating scale score (IRLS) Mean difference -10.0, p=0.01 | Inconclusive | High |
| Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis–Ekbom disease) Jan-Peer Elshoff et al.. Sleep Medicine 32 48-55. (2017) | rotigotine | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLS) | Inconclusive | High |
| A method to switch from oral dopamine agonists to rotigotine in patients with restless legs syndrome and mild augmentation John W. Winkelman et al.. Sleep Medicine 24 18-23. (2016) | rotigotine | Quasi-Experimental | — | International Restless Legs Syndrome (IRLS) severity score Mean difference -6.70, p=0.00 | Favors treatment | High |
| Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome Yong Won Cho et al.. Sleep Medicine 25 16-23. (2016) | iron | RCT | 64 | International RLS Severity Scale (IRLSS) change from baseline Mean difference -1.28, p=0.47 | No difference | Some Concerns |
| Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel Diego Garcia-Borreguero et al.. Sleep Medicine 34 105-108. (2017) | perampanel | Quasi-Experimental | — | IRLS (International Restless Legs Syndrome) total score | Favors treatment | High |
| Willis-Ekbom disease/restless legs syndrome in patients with opioid withdrawal Ravi Gupta et al.. Sleep Medicine 45 39-43. (2018) | pregabalin | Quasi-Experimental | — | Development of RLS during opioid withdrawal (prevalence) | Inconclusive | High |
| Efficacy of ferric carboxymaltose (FCM) 500 mg dose for the treatment of Restless Legs Syndrome Yong Won Cho et al.. Sleep Medicine 42 7-12. (2018) | iron | RCT | 64 | International RLS Severity Scale (IRLSS) change from baseline Mean difference -3.50, p=0.10 | No difference | Some Concerns |
| Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis Diego Garcia-Borreguero et al.. Sleep Medicine 45 94-97. (2018) | dipyridamole | Quasi-Experimental | — | International Restless Legs Syndrome (IRLS) total score Mean difference -12.7, p=0.01 | Inconclusive | High |
| Impaired short-term plasticity in restless legs syndrome: a pilot rTMS study Giuseppe Lanza et al.. Sleep Medicine 46 1-4. (2018) | repetitive transcranial magnetic stimulation (rtms) | Quasi-Experimental | 23 | Resting Motor Threshold (rMT) | No difference | High |
| Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome John W. Winkelman et al.. Sleep Medicine 48 1-7. (2018) | gabapentin enacarbil | Crossover | 131 | International Restless Legs Syndrome Rating Scale (IRLS) total score Mean difference -6.55 | Favors treatment | Some Concerns |
| Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment Diego Garcia-Borreguero et al.. Sleep Medicine 55 74-80. (2019) | gabapentin enacarbil | Crossover | 39 | International Restless Legs Syndrome Scale (IRLS) total score Mean difference -9.37, p=0.00 | Favors treatment | Some Concerns |
| Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome Celia Garcia-Malo et al.. Sleep Medicine 66 123-129. (2020) | iron | Quasi-Experimental | — | Substantia Nigra Echogenicity Index (SNEI) | Inconclusive | High |
| Cognitive behavioral therapy for insomnia in restless legs syndrome patients Mei Ling Song et al.. Sleep Medicine 74 227-234. (2020) | cognitive behavioral therapy for insomnia | RCT | 40 | Insomnia Severity Index (Korean version) Mean difference -8.40, p=0.00 | Favors treatment | High |
| Altered cortical gray matter volume and functional connectivity after transcutaneous spinal cord direct current stimulation in idiopathic restless legs syndrome Li Wang et al.. Sleep Medicine 74 254-261. (2020) | transcutaneous spinal cord direct current stimulation | RCT | 30 | International RLS Rating Scale (IRLS-RS) Mean difference -8.40 | Inconclusive | High |
| Efficacy and safety of TOMAC for treatment of medication-naïve and medication-refractory restless legs syndrome: A randomized clinical trial and meta-analysis Haramandeep Singh et al.. Sleep Medicine 122 141-148. (2024) | tonic motor activation (tomac) | RCT | 45 | IRLS total score change from study entry to Week 4 (all participants) Mean difference -4.42 (-7.26–-1.57), p=0.00 | Favors treatment | Low |
| Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial Trenkwalder C. et al.. The Lancet Neurology 7(7) 595-604. (2008) | rotigotine | RCT | 458 | IRLS sum score - change from baseline to end of maintenance Mean difference -5.10 (-7.60–-2.70), p=0.00 | Favors treatment | Some Concerns |
| The Treatment of the Restless Legs Syndrome with Clonazepam: A Prospective Controlled Study Dan Boghen et al.. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 13(3) 245-247. (1986) | clonazepam | Crossover | 6 | Daily self-rating discomfort score (5-point scale) | No difference | High |
| Effectiveness of aripiprazole in treatment of adults with attention deficit disorder and restless legs syndrome Kikukawa S.. The International Journal of Neuropsychopharmacology 11(03) 439-40. (2008) | aripiprazole | — | — | ADD symptoms (organization, planning, procrastination) | Inconclusive | High |
| In vivo
Mesolimbic D2/3 Receptor Binding Predicts Posttherapeutic Clinical Responses in Restless Legs Syndrome: A Positron Emission Tomography Study Yumi Oboshi et al.. Journal of Cerebral Blood Flow & Metabolism 32(4) 654-662. (2012) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLSS) score | Inconclusive | High |
| Incidence of periodic leg movements and of the restless legs syndrome during sleep following acute physical activity in spinal cord injury subjects de Mello MT et al.. Spinal Cord 34(5) 294-296. (1996) | acute physical activity | Crossover | — | Number of leg movements (PLM + RLS) Mean difference -23.0, p=0.03 | Favors treatment | High |
| A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients Micah L. Thorp et al.. American Journal of Kidney Diseases 38(1) 104-108. (2001) | gabapentin | Crossover | 16 | RLS symptom severity questionnaire score (parametric) Mean difference -2.80, p=0.01 | Favors treatment | Some Concerns |
| A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome James A. Sloand et al.. American Journal of Kidney Diseases 43(4) 663-670. (2004) | iron | RCT | 25 | RLS symptom severity score | Favors treatment | Some Concerns |
| An Intradialysis Diagnostic Test for Restless Legs Syndrome: A Pilot Study Akito Kume et al.. American Journal of Kidney Diseases 54(2) 318-326. (2009) | pergolide | Quasi-Experimental | — | Presence of periodic limb movements (PLMs) on 30-minute SIT during dialysis (diagnostic accuracy) | Inconclusive | High |
| Rotigotine in Hemodialysis-Associated Restless Legs Syndrome: A Randomized Controlled Trial Yves Dauvilliers et al.. American Journal of Kidney Diseases 68(3) 434-443. (2016) | rotigotine | RCT | 30 | Periodic Limb Movement Index (PLMI) ratio (end of maintenance to baseline) Rate ratio 0.44 (0.22–0.88), p=0.02 | Favors treatment | Some Concerns |
| A Randomized, Open Label, Exploratory Trial Comparing Efficacy of Amantadine and Ropinirole in Restless Legs Syndrome Govind Madhaw et al.. Sleep Science 16(02) 174-182. (2023) | ropinirole | RCT | 46 | International RLS Study Group Rating Scale (IRLS) score Mean difference 8.00, p=0.00 | Favors treatment | Some Concerns |
| Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome Richard P. Allen et al.. New England Journal of Medicine 370(7) 621-631. (2014) | pregabalin | RCT | 731 | IRLS Study Group Rating Scale score Mean difference -4.50 (-5.90–-3.20), p=0.00 | Favors treatment | Some Concerns |
| Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS William G. Ondo et al.. International Journal of Neuroscience 132(8) 778-782. (2022) | ecopipam | Crossover | 10 | International Restless Legs Syndrome Rating Scale (IRLS) Mean difference -2.20 | No difference | Some Concerns |
| Usefulness of electronic stimulation in restless legs syndrome: a pilot study Yong Won Cho et al.. International Journal of Neuroscience 132(12) 1225-1228. (2022) | electronic stimulation | RCT | 48 | Visual Analogue Scale for RLS symptoms Mean difference 2.42, p=0.75 | Mixed | High |
| Gabapentin Versus Levodopa for the Treatment of Restless Legs Syndrome in Hemodialysis Patients: An Open‐Label Study Hasan Micozkadıoglu et al.. Renal Failure 26(4) 393-397. (2004) | gabapentin | Crossover | 15 | RLS severity score | Favors treatment | High |
| Efficacy of an Eight-Week Yoga Intervention on Symptoms of Restless Legs Syndrome (RLS): A Pilot Study Kim E. Innes et al.. The Journal of Alternative and Complementary Medicine 19(6) 527-535. (2013) | yoga | Quasi-Experimental | 13 | International RLS Rating Scale (IRLS) Total Score Mean difference -10.3, p=0.01 | Inconclusive | High |
| The Effect of Cannabidiol for Restless Legs Syndrome/Willis-Ekbom Disease in Parkinson's Disease Patients with REM Sleep Behavior Disorder: A
Post Hoc
Exploratory Analysis of Phase 2/3 Clinical Trial Carlos Mauricio Oliveira de Almeida et al.. Cannabis & Cannabinoid Research 8(2) 374-378. (2023) | cannabidiol | RCT | 18 | RLS/WED severity by IRLSSG rating scale | No difference | Some Concerns |
| An Exploratory Randomized Controlled Trial of a 12-Week Yoga Versus Educational Film Program for the Management of Restless Legs Syndrome: Feasibility and Acceptability Terry Kit Selfe et al.. Journal of Integrative and Complementary Medicine 28(4) 309-319. (2022) | yoga | RCT | 41 | Class attendance rate | Inconclusive | Some Concerns |
| Efficacy and Safety of Acupuncture for Restless Legs Syndrome in Patients with End-Stage Renal Disease: A Randomized-Controlled Trial at Hospital-Based Hemodialysis Center Jia-Ming Chen et al.. Journal of Integrative and Complementary Medicine 30(10) 978-985. (2024) | acupuncture | RCT | 41 | International Restless Legs Syndrome Rating Scale (IRLSRS) Mean difference -3.20, p=0.00 | Favors treatment | Some Concerns |
| A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome Giannaki CD et al.. Nephrology Dialysis Transplantation 28(11) 2834-2840. (2013) | progressive aerobic exercise training | RCT | 24 | RLS symptom severity (IRLS score) Mean difference -11.1, p=0.02 | Favors treatment | Some Concerns |
| Successful Treatment of the Idiopathic Restless Legs Syndrome in a Randomized Double-Blind Trial of Oxycodone Versus Placebo Arthur S. Walters et al.. Sleep 16(4) 327-332. (1993) | oxycodone | Crossover | 11 | Leg sensations (paresthesias) - subjective daily rating Mean difference -1.32, p=0.01 | Favors treatment | Some Concerns |
| L-Dopa Therapy of Uremic and Idiopathic Restless Legs Syndrome: A Double-Blind, Crossover Trial Trenkwalder C. et al.. Sleep 18(8) 681-688. (1995) | levodopa | Crossover | 28 | Frequency of PLM (polysomnography, total night) Mean difference -132, p=0.00 | Favors treatment | Some Concerns |
| Randomized, Double-Blind, Placebo-Controlled Study of Clonidine in Restless Legs Syndrome Wagner ML et al.. Sleep 19(1) 52-8. (1996) | clonidine | Crossover | 10 | Paresthesias (leg sensations) subjective rating Mean difference -1.40, p=0.02 | Favors treatment | Some Concerns |
| 10.1093/sleep/19.3.214 | levodopa/carbidopa | Crossover | 8 | Leg movements per hour of sleep (LM Index) Mean difference -40.0, p=0.01 | Favors treatment | Some Concerns |
| Effect of Pergolide on Restless Legs and Leg Movements in Sleep in Uremic Patients Jacek Pieta et al.. Sleep 21(6) 617-622. (1998) | pergolide | Crossover | 14 | Percentage of first hour in bed with increased leg EMG activity (PSG) Mean difference -8.60, p=0.05 | No difference | Some Concerns |
| Rapid Onset of Action of Levodopa in Restless Legs Syndrome: A Double-Blind, Randomized, Multicenter, Crossover Trial Heike Beneš et al.. Sleep 22(8) 1073-1081. (1999) | levodopa/benserazide | Crossover | 35 | PLMs per hour in bed Mean difference -26.8, p=0.00 | Favors treatment | Some Concerns |
| 10.1093/sleep/23.3.1b | cabergoline | Quasi-Experimental | — | Number of Periodic Leg Movements (PLM) during time in bed Mean difference -169, p=0.00 | Inconclusive | High |
| Cabergoline is an Effective Single-drug Treatment for Restless Legs Syndrome: Clinical and Actigraphic Evaluation Marco Zucconi et al.. Sleep 26(7) 815-818. (2003) | cabergoline | Quasi-Experimental | 12 | International RLS Study Group Rating Scale score Mean difference -11.8, p=0.01 | Favors treatment | High |
| Long-term Safety and Efficacy of Cabergoline for the Treatment of Idiopathic Restless Legs Syndrome: Results from an Open-Label 6-Month Clinical Trial Heike Beneš et al.. Sleep 27(4) 674-682. (2004) | cabergoline | Quasi-Experimental | — | Severity of RLS during the night (RLS-6 scale) | Inconclusive | High |
| Ropinirole Decreases Periodic Leg Movements and Improves Sleep Parameters in Patients with Restless Legs Syndrome Allen R. et al.. Sleep 27(5) 907-914. (2004) | ropinirole | RCT | 65 | Periodic limb movements of sleep per hour (PLMS/hour) Mean difference -27.2 (-39.1–-15.4), p=0.00 | Favors treatment | Some Concerns |
| A Randomized, Double-Blind, Placebo-Controlled, Crossover Study of Xp13512/Gsk1838262 in the Treatment of Patients With Primary Restless Legs Syndrome Kushida CA et al.. Sleep 32(2) 159-168. (2009) | xp13512 (gabapentin enacarbil) | Crossover | 38 | Change from baseline IRLS total score at Day 14 Mean difference -10.2, p=0.00 | Favors treatment | Some Concerns |
| Acute Dopamine-Agonist Treatment in Restless Legs Syndrome: Effects on Sleep Architecture and NREM Sleep Instability Raffaele Ferri et al.. Sleep 33(6) 793-800. (2010) | pramipexole | RCT | 34 | Periodic Leg Movements during Sleep (PLMS) Index Mean difference -46.5 | Favors treatment | Some Concerns |
| 10.1093/sleep/9.3.385 | clonazepam and temazepam | Crossover | 10 | Sleep latency Mean difference -9.30 | Favors treatment | Some Concerns |
| 0791 Effects of Low Frequency Electrical Stimulators as Nonpharmacological Treatment in Restless Legs Syndrome Y Cho et al.. Sleep 43(Supplement_1) A301-A301. (2020) | low frequency electrical stimulators | RCT | 46 | RLS symptom severity | Favors treatment | High |
| 0796 Dipyridamole for the Treatment of RLS: Preliminary Results of a Cross-Over, Placebo-Controlled, Double-Blind Trial Diego Garcı́a-Borreguero et al.. Sleep 43(Supplement_1) A303-A303. (2020) | dipyridamole | Crossover | 15 | IRLS total score (International Restless Legs Syndrome rating scale) Mean difference -6.82, p=0.05 | No difference | Some Concerns |
| 0802 To Examine the Effect of Gabapentin Enacarbil in Primary Restless Legs Syndrome Patients Who are on Dopaminergic Agents and Exhibiting Augmentation Pradeep C. Bollu et al.. Sleep 43(Supplement_1) A305-A305. (2020) | gabapentin enacarbil | Quasi-Experimental | — | Augmentation Severity Rating Scale (ASRS) | Favors treatment | High |
| 0809 A Randomized Double-blind, Placebo Controlled Trial With Cross-over, To Assess The Efficacy Of Correcting Vitamin D Deficiency In Improving The Symptoms Of Restless Legs Syndrome (RLS) Jennie Wong et al.. Sleep 43(Supplement_1) A307-A308. (2020) | vitamin d3 | Crossover | 2 | RLS symptom severity (weekly iRLS questionnaire) | Inconclusive | Some Concerns |
| 531 Efficacy of a physical activity intervention for managing restless legs syndrome in multiple sclerosis: A pilot RCT Katie Cederberg et al.. Sleep 44(Supplement_2) A209-A209. (2021) | physical activity intervention | RCT | 15 | Overall RLS severity | Favors treatment | Some Concerns |
| 0710 Effects of tonic motor activation (TOMAC) therapy on sleep quality for refractory restless legs syndrome Richard Bogan et al.. SLEEP 46(Supplement_1) A311-A312. (2023) | tonic motor activation (tomac) therapy | RCT | 133 | MOS-Sleep Sleep Problems Index I (MOS-I) Mean difference -9.00, p=0.00 | Favors treatment | Some Concerns |
| 0713 Long-term response to tonic motor activation (TOMAC) therapy for refractory restless legs syndrome Asim Roy et al.. SLEEP 46(Supplement_1) A313-A313. (2023) | tonic motor activation (tomac) | RCT | 133 | Clinician Global Impressions-Improvement (CGI-I) responder rate | Inconclusive | Some Concerns |
| Change of iron content in brain regions after intravenous iron therapy in restless legs syndrome: quantitative susceptibility mapping study Tae-Joon Kim et al.. SLEEP 46(8) zsad154. (2023) | iron | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLS) Mean difference -10.2, p=0.00 | Favors treatment | High |
| Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study Roy A. et al.. SLEEP 46(10) zsad188. (2023) | tonic motor activation (tomac) | Quasi-Experimental | — | Clinical Global Impressions-Improvement (CGI-I) Responder Rate | Favors treatment | High |
| Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial Bogan RK et al.. SLEEP 46(10) zsad190. (2023) | tonic motor activation (tomac) | RCT | 133 | Clinical Global Impressions-Improvement (CGI-I) responder rate at Week 4 Risk difference 0.28 (0.14–0.43), p=0.00 | Favors treatment | Low |
| 0390 Efficacy of Suvorexant for Insomnia Disorder in Well-controlled Restless Legs Syndrome John Winkelman et al.. SLEEP 47(Supplement_1) A167-A168. (2024) | suvorexant | Crossover | 34 | Actigraphically-derived Total Sleep Time (TST) | No difference | Some Concerns |
| 0687 RLS Treatment Reduces Nighttime Agitation and Increases Sleep Duration in Older Adults with Alzheimer's Disease Kathy Richards et al.. SLEEP 47(Supplement_1) A294-A295. (2024) | gabapentin enacarbil | RCT | 147 | Nighttime agitation Mean difference -2.21, p=0.00 | Favors treatment | Some Concerns |
| 0704 Comparative Efficacy of Tonic Motor Activation for Medication-Naïve and Dopaminergic-Treated Restless Legs Syndrome Mark Buchfuhrer et al.. SLEEP 47(Supplement_1) A301-A301. (2024) | tonic motor activation (tomac) | RCT | — | International RLS Scale (IRLS) score change — Trial 1 (crossover), drug-naive subgroup Mean difference -4.20, p=0.01 | Favors treatment | Some Concerns |
| 0712 Tonic Motor Activation for Restless Legs Syndrome Is Compatible with Sleep Onset and Reduces Periodic Leg Movements Stephanie Rigot et al.. SLEEP 47(Supplement_1) A304-A305. (2024) | tonic motor activation (tomac) | Quasi-Experimental | 23 | Periodic leg movements during sleep (PLMS) frequency Mean difference -27.6, p=0.01 | Favors treatment | High |
| 0903 Sex-Related Differences in Periodic Leg Movements Across the Lifespan and in Their Response to Treatment in RLS Maria Mogavero et al.. SLEEP 48(Supplement_1) A392-A392. (2025) | pramipexole and ropinirole | Quasi-Experimental | 41 | Total leg movements | Inconclusive | High |
| 0664 The Effect Of Gabapentin Enacarbil On Dopaminergic Augmentation In Patients With Primary Restless Legs Syndrome M. Goyal et al.. Sleep 41(suppl_1) A246-A246. (2018) | gabapentin enacarbil | Quasi-Experimental | — | International Restless Legs Syndrome Rating Scale (IRLS) score | Inconclusive | High |
| Striatal histamine mechanism in the pathogenesis of restless legs syndrome Yuan-Yang Lai et al.. Sleep 43(2) zsz223. (2019) | thioperamide | Quasi-Experimental | — | Periodic Leg Movements in Sleep index (PLMSI) - 8-hour post-injection | Inconclusive | High |
| 0747 cranial electrotherapy for military beneficiaries with restless leg syndrome TL Yost et al.. Sleep 40(suppl_1) A277-A277. (2017) | cranial electrical stimulation | Crossover | — | International Restless Legs Syndrome Scale (IRLS) — change from baseline Mean difference -11.1, p=0.00 | Favors treatment | Some Concerns |
| Restless Legs Syndrome Treatment with Dopaminergic Drugs Levket Akpinar. Clinical Neuropharmacology 10(1) 69-79. (1987) | levodopa/benserazide | — | — | — | — | — |
| Exercise Mediates The Association Between Sleep Quality And Restless Legs Syndrome Severity Melissa M. Aukerman et al.. Medicine & Science in Sports & Exercise 37(Supplement) S127. (2005) | aerobic and resistance exercise | RCT | — | — | — | — |
| Ropinirole as a Treatment of Restless Legs Syndrome in Patients on Chronic Hemodialysis Maria Teresa Pellecchia et al.. Clinical Neuropharmacology 27(4) 178-181. (2004) | ropinirole | RCT | — | — | — | — |
| The Effect of Cold Dialysis in Motor and Sensory Symptoms of RLS/WED Occurring During Hemodialysis: A Double-Blind Study Giorgos K. Sakkas et al.. ASAIO Journal 64(1) 110-114. (2018) | cold dialysis | — | — | — | — | — |
| Intradialytic Aerobic Exercise Training Ameliorates Symptoms of Restless Legs Syndrome and Improves Functional Capacity in Patients on Hemodialysis Giorgos K. Sakkas et al.. ASAIO Journal 54(2) 185-190. (2008) | aerobic exercise training | — | — | — | — | — |
| Non-Pharmacological Management of Periodic Limb Movements During Hemodialysis Session in Patients With Uremic Restless Legs Syndrome Christoforos D. Giannaki et al.. ASAIO Journal 56(6) 538-542. (2010) | exercise (cycling) | — | — | — | — | — |
| Effects of acupuncture on sensory symptoms and motor signs in patients with restless legs syndrome: A crossover randomized controlled trial Takero Fukutome et al.. Medicine 101(51) e32317. (2022) | acupoint injection | Crossover | 8 | Mean Leg Discomfort Score (MLDS) during SIT Mean difference -42.4 (-59.2–-19.8), p=0.00 | Mixed | Some Concerns |
| Hydrotherapy and acupressure in restless legs syndrome: A randomized, controlled, 3-armed, explorative clinical trial Julia Kubasch et al.. Medicine 102(26) e34046. (2023) | hydrotherapy and acupressure | RCT | 51 | RLS Symptom Severity (International Restless Legs Syndrome Study Group Rating Scale) | Inconclusive | High |
| Effect of “He Tiao Du Ren An Shen Acupuncture” on restless leg syndrome: A randomized trial Xin-Rui Guan et al.. Medicine 103(39) e39926. (2024) | acupuncture (he tiao du ren an shen) | RCT | 66 | International Restless Leg Syndrome Scale (IRLS) score Mean difference -0.30, p=0.85 | No difference | Some Concerns |
| Sequential Compression Devices for Treatment of Restless Legs Syndrome Arn H. Eliasson et al.. Medicine 86(6) 317-323. (2007) | pneumatic sequential compression devices | Quasi-Experimental | — | RLS Severity (International RLS Study Group Rating Scale) Mean difference -16.0, p=0.00 | Inconclusive | High |
| 10.1097/nen.0b013e3180517b5f | ropinirole | — | — | — | — | — |
| Entacapone Prolongs the Reduction of PLM by Levodopa/Carbidopa in Restless Legs Syndrome Olli Polo et al.. Clinical Neuropharmacology 30(6) 335-344. (2007) | levodopa/carbidopa/entacapone | Crossover | 28 | Periodic limb movements per hour during total sleep time (PLM/h TST) Mean difference -13.1, p=0.05 | No difference | Some Concerns |
| Patient- and Physician-Rated Measures Demonstrate the Effectiveness of Ropinirole in the Treatment of Restless Legs Syndrome Clete A. Kushida et al.. Clinical Neuropharmacology 31(5) 281-286. (2008) | ropinirole | RCT | 362 | Change from baseline in IRLS total score Mean difference -4.11 (-6.08–-2.14), p=0.00 | Favors treatment | Some Concerns |
| Gabapentin Enacarbil in Restless Legs Syndrome Arthur S. Walters et al.. Clinical Neuropharmacology 32(6) 311-320. (2009) | gabapentin enacarbil | RCT | 95 | Change from baseline IRLS total score at day 14 (end of treatment) Mean difference -7.20, p=0.00 | Favors treatment | Some Concerns |
| Dopaminergic Treatment in Idiopathic Restless Legs Syndrome Ulf Kallweit et al.. Clinical Neuropharmacology 33(6) 276-278. (2010) | pramipexole | Crossover | 37 | Epworth Sleepiness Scale (ESS) score | No difference | Some Concerns |
| A 52-Week Study of Gabapentin Enacarbil in Restless Legs Syndrome Aaron L. Ellenbogen et al.. Clinical Neuropharmacology 34(1) 8-16. (2011) | gabapentin enacarbil | Quasi-Experimental | — | International Restless Legs Scale (IRLS) total score - change from parent study baseline | Inconclusive | High |
| A Randomized, Double-Blind, Placebo-Controlled, Dose-Response Study to Assess the Pharmacokinetics, Efficacy, and Safety of Gabapentin Enacarbil in Subjects With Restless Legs Syndrome Ritu Lal et al.. Clinical Neuropharmacology 35(4) 165-173. (2012) | gabapentin enacarbil | RCT | 217 | IRLS Rating Scale total score change from baseline at week 12 Mean difference -4.50 | Inconclusive | Some Concerns |
| Influence of Cabergoline on Motor Excitability in Patients With Restless Legs Syndrome Gorsler A. et al.. Journal of Clinical Neurophysiology 24(6) 456-460. (2007) | cabergoline | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLSSGRS) | Favors treatment | High |
| Comparison the effect of valerian and gabapentin on RLS and sleep quality in hemodialysis patients: A randomized clinical trial Iman Hajizadeh et al.. Therapeutic Apheresis and Dialysis 27(4) 621-628. (2023) | gabapentin | Crossover | 40 | Restless Legs Syndrome severity score Mean difference 0.12, p=0.96 | No difference | High |
| Comparison of the efficacies of oral iron and pramipexole for the treatment of restless legs syndrome patients with low serum ferritin Lee CS et al.. European Journal of Neurology 21(2) 260-266. (2014) | pramipexole | RCT | 30 | International RLS Study Group Rating Scale for Severity (IRLS) score Mean difference -0.40, p=0.99 | No difference | High |
| Carbamazepine Therapy in Restless Legs: Discrimination between Responders and Non‐responders Larsen S. et al.. Acta Medica Scandinavica 218(2) 223-227. (1985) | carbamazepine | RCT | 174 | Frequency of restless legs attacks per week | Inconclusive | Some Concerns |
| High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron Birgegård G. et al.. Vox Sanguinis 99(4) 354-361. (2010) | iron | RCT | 120 | P-ferritin (all subjects) Mean difference 7.20, p=0.00 | Favors treatment | Some Concerns |
| Periodic Leg Movements in Sleep with Restless Legs Syndrome: Effect of Clonazepam Treatment Jun Horiguchi et al.. Psychiatry and Clinical Neurosciences 46(3) 727-732. (1992) | clonazepam | Quasi-Experimental | — | Total number of periodic leg movements in sleep (left leg) | No difference | High |
| Actometry in measuring the symptom severity of restless legs syndrome Tuisku K. et al.. European Journal of Neurology 12(5) 385-387. (2005) | pramipexole | Quasi-Experimental | — | Nocturnal lower-limb activity | Inconclusive | High |
| The powerful pre‐treatment effect: placebo responses in restless legs syndrome trials de la Fuente-Fernández R.. European Journal of Neurology 19(10) 1305-1310. (2012) | rotigotine | RCT | — | Change in IRLS sum score from baseline to end of maintenance (placebo arm, pre-treated patients, SP790) | Favors treatment | Some Concerns |
| Orphenadrine citrate (norflex) for the treatment of “restless legs” and related syndromes Roy J. Popkin. Journal of the American Geriatrics Society 19(1) 76-79. (1971) | orphenadrine citrate | Quasi-Experimental | — | Overall symptomatic response to orphenadrine citrate | Inconclusive | High |
| Clonazepam and vibration in restless legs syndrome Pasquale Montagna et al.. Acta Neurologica Scandinavica 69(6) 428-430. (1984) | clonazepam | Crossover | 6 | Quality of sleep (week-score) | No difference | Some Concerns |
| Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome Nardone R. et al.. Acta Neurologica Scandinavica 114(4) 244-249. (2006) | cabergoline | Quasi-Experimental | — | Short Latency Intracortical Inhibition (SICI) Mean difference 31.0, p=0.03 | Inconclusive | High |
| PTPRD as a candidate druggable target for therapies for restless legs syndrome? Milca A. Morais et al.. Journal of Sleep Research 30(4) e13216. (2021) | pramipexole | Quasi-Experimental | 16 | Total Sleep Time (TST) Mean difference 32.5, p=0.01 | Favors treatment | High |
| Transcutaneous electrical nerve stimulation in the management of restless legs syndrome symptoms: A single‐blind, parallel‐group clinical study Zeynep Selcan Şanli et al.. Journal of Sleep Research 33(5) e14167. (2024) | pramipexole | RCT | 50 | International Restless Legs Syndrome Rating Scale (IRLSRS) Mean difference -3.18, p=0.03 | Favors treatment | Some Concerns |
| Sex‐based disparities in dopamine agonist response in patients with restless legs syndrome Maria P. Mogavero et al.. Journal of Sleep Research 34(2) e14311. (2025) | pramipexole and ropinirole | Quasi-Experimental | 41 | PLMS index (periodic leg movements during sleep index) Mean difference -13.4, p=0.00 | Inconclusive | High |
| Treatment of the restless legs syndrome with carbamazepine: a double blind study. Telstad W. et al.. BMJ 288(6415) 444-446. (1984) | carbamazepine | RCT | 174 | Severity of symptoms of restless legs syndrome | Favors treatment | Some Concerns |
| Restless legs syndrome in patients with type 2 diabetes: effectiveness of pramipexole therapy Shin-Ichi Harashima et al.. BMJ Supportive & Palliative Care 6(1) 89-93. (2016) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Rating Scale (IRLS) score | Inconclusive | High |
| Apomorphine in idiopathic restless legs syndrome: an exploratory study Tribl GG et al.. Journal of Neurology, Neurosurgery & Psychiatry 76(2) 181-185. (2005) | apomorphine | Crossover | 9 | Subjective leg symptoms (visual analogue scale) Mean difference -3.20, p=0.01 | Favors treatment | High |
| Cognitive behavioural group therapy to improve patients' strategies for coping with restless legs syndrome: a proof-of-concept trial Hornyak M. et al.. Journal of Neurology, Neurosurgery & Psychiatry 79(7) 823-825. (2008) | cognitive behavioural therapy | Quasi-Experimental | — | Quality of Life in Restless Legs Syndrome (QoL-RLS) total score Mean difference -5.20, p=0.00 | Inconclusive | High |
| Response to ropinirole in restless legs syndrome is independent of baseline serum ferritin Morgan JC et al.. Journal of Neurology, Neurosurgery & Psychiatry 79(8) 964-965. (2008) | ropinirole | RCT | 550 | Change from baseline in International Restless Legs Scale (IRLS) total score at week 12 LOCF Mean difference -2.80 (-5.40–-0.20), p=0.04 | Favors treatment | Some Concerns |
| The Effects of a Gentle Yoga Program on Sleep, Mood, and Blood Pressure in Older Women with Restless Legs Syndrome (RLS): A Preliminary Randomized Controlled Trial Kim E. Innes et al.. Evidence-Based Complementary and Alternative Medicine 2012 1-14. (2012) | gentle yoga | RCT | 20 | Pittsburgh Sleep Quality Index - Global Score Std. mean difference 2.59, p=0.01 | Favors treatment | Some Concerns |
| Aerobic Exercise Improves Signs of Restless Leg Syndrome in End Stage Renal Disease Patients Suffering Chronic Hemodialysis Mojgan Mortazavi et al.. The Scientific World Journal 2013(1) 628142. (2013) | aerobic exercise | RCT | 26 | Restless leg syndrome severity score Mean difference -4.97, p=0.00 | Favors treatment | High |
| Actigraph Evaluation of Acupuncture for Treating Restless Legs Syndrome Weidong Pan et al.. Evidence-Based Complementary and Alternative Medicine 2015 1-7. (2015) | acupuncture | RCT | 38 | Nocturnal Activity (NA) — leg actigraph zero-crossing counts during all nocturnal bedtime | No difference | High |
| Effect of Local Warm Compression on Restless Leg Syndrome and Fatigue among Critical Care Nurses: A Parallel Randomized Clinical Trial Maryam Ameri et al.. Critical Care Research and Practice 2022 1-7. (2022) | warm compression | RCT | 120 | Restless Legs Syndrome severity Mean difference 0.78, p=0.41 | No difference | Some Concerns |
| A Randomized, Double-Blind Placebo-Controlled Trial of Iron in Restless Legs Syndrome Bradley J. Davis et al.. European Neurology 43(2) 70-75. (2000) | iron | RCT | 28 | Quality of sleep (VAS 1) — improvement (dichotomous) | No difference | Some Concerns |
| Sleep Laboratory Studies in Restless Legs Syndrome Patients as Compared with Normals and Acute Effects of Ropinirole Saletu M. et al.. Neuropsychobiology 41(4) 190-199. (2000) | ropinirole | Crossover | 12 | PLM per hour of total sleep time (PLM/h TST) Mean difference -29.4, p=0.01 | Favors treatment | High |
| Clinical Data on Restless Legs Syndrome: A Dose-Finding Study with Cabergoline Karin Stiasny. European Neurology 46(Suppl. 1) 24-26. (2001) | cabergoline | RCT | 86 | Severity of RLS symptoms at night (primary endpoint) | Inconclusive | Some Concerns |
| Low-Dose Pramipexole in the Management of Restless Legs Syndrome Karin Stiasny-Kolster et al.. Neuropsychobiology 50(1) 65-70. (2004) | pramipexole | Quasi-Experimental | — | IRLS Severity Scale (global RLS severity) Mean difference -22.5, p=0.00 | Inconclusive | High |
| The Acute Effect of a Low Dosage of Pramipexole on Severe Idiopathic Restless Legs Syndrome: An Open-Label Trial Giovanni Merlino et al.. Neuropsychobiology 54(3) 195-200. (2006) | pramipexole | Crossover | 10 | Visual Analog Scale for RLS sensory symptoms Mean difference -5.80, p=0.00 | Favors treatment | High |
| Excessive Daytime Sleepiness in Idiopathic Restless Legs Syndrome: Characteristics and Evolution under Dopaminergic Treatment Ulf Kallweit et al.. European Neurology 62(3) 176-179. (2009) | dopaminergic agents | Quasi-Experimental | — | International RLS Study Group Rating Scale (IRLS) score Mean difference -7.30, p=0.00 | Favors treatment | High |
| Efficacy, Safety and Dose-Response of Pramipexole in Japanese Patients with Primary Restless Legs Syndrome: Randomized Trial Yuichi Inoue et al.. Neuropsychobiology 63(1) 35-42. (2011) | pramipexole | RCT | 154 | IRLS Total Score Mean difference 0.20 | No difference | Some Concerns |
| Investigating Homeopathic Verum and Placebo Globules with UV Spectroscopy Sabine D. Klein et al.. Complementary Medicine Research 20(4) 295-297. (2013) | calcium carbonate / quercus e cortice 6x | RCT | — | UV absorbance at 200-290 nm (corrected average) | Inconclusive | High |
| Lack of Pharmacokinetic Interactions Between Transdermal Rotigotine and Oral Levodopa/Carbidopa Marina Braun et al.. The Journal of Clinical Pharmacology 49(9) 1047-1055. (2009) | rotigotine | Crossover | 24 | Levodopa AUC at steady state (AUCss) Odds ratio 0.97 | Inconclusive | Some Concerns |
| Population Pharmacokinetics and Pharmacodynamics of Gabapentin After Administration of Gabapentin Enacarbil Ritu Lal et al.. The Journal of Clinical Pharmacology 53(1) 29-40. (2013) | gabapentin enacarbil | RCT | 994 | Change from baseline in IRLS total score at week 12/end of treatment Mean difference -6.16 | Favors treatment | Some Concerns |
| Clinical and electrophysiological impact of repetitive low-frequency transcranial magnetic stimulation on the sensory–motor network in patients with restless legs syndrome Giuseppe Lanza et al.. Therapeutic Advances in Neurological Disorders 11 1756286418759973. (2018) | repetitive transcranial magnetic stimulation (rtms) | Crossover | 23 | Subjective quality of initiating and maintaining sleep | Inconclusive | Some Concerns |
| Effect of Oral Iron Administration on Mental State in Children With Low Serum Ferritin Concentration Katsunaka Mikami et al.. Global Pediatric Health 6 2333794X19884816. (2019) | iron | Quasi-Experimental | — | Clinical Global Impression Severity (CGI) | Favors treatment | High |
| A randomized controlled pilot trial of positional release manipulation (counterstrain) in the treatment of restless legs syndrome Roderic MacDonald et al.. International Musculoskeletal Medicine 33(1) 21-25. (2011) | counterstrain manipulation | RCT | 40 | International Restless Legs Study Group Severity Scale | Inconclusive | High |
| Counterstrain manipulation in the treatment of restless legs syndrome: A pilot single-blind randomized controlled trial; the CARL Trial Theo Peters et al.. International Musculoskeletal Medicine 34(4) 136-140. (2012) | counterstrain manipulation | RCT | 39 | International Restless Legs Scale (IRLS) total score change from baseline to week 6 Mean difference -8.06 (-13.0–-3.15), p=0.00 | Favors treatment | Some Concerns |
| Comparison of the bioavailability and adhesiveness of different rotigotine transdermal patch formulations Jan-Peer Elshoff et al.. Current Medical Research and Opinion 29(12) 1657-1662. (2013) | rotigotine | Crossover | — | Bioequivalence: AUC(0-tz) ratio of unconjugated rotigotine plasma concentrations | Inconclusive | Some Concerns |
| Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study Diego Garcia-Borreguero et al.. Current Medical Research and Opinion 32(1) 77-85. (2016) | rotigotine | RCT | 150 | International Restless Legs Syndrome Rating Scale (IRLS) sum score Mean difference -0.27 (-2.96–2.42), p=0.85 | No difference | Some Concerns |
| Effect of exercise training and dopamine agonists in patients with uremic restless legs syndrome: a six-month randomized, partially double-blind, placebo-controlled comparative study Christoforos D. Giannaki et al.. BMC Nephrology 14(1) 194. (2013) | ropinirole | RCT | 32 | RLS symptom severity (IRLS score) Mean difference -12.0, p=0.01 | Favors treatment | Some Concerns |
| Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch Birgit Högl et al.. BMC Neurology 10(1) 86. (2010) | rotigotine | Quasi-Experimental | — | International RLS Study Group Severity Rating Scale total score (IRLS) | Inconclusive | High |
| OA14.03. Effects of yoga on sleep, mood, and related outcomes in older women with Restless Legs Syndrome: a nested randomized controlled trial (RCT) Kim Innes et al.. BMC Complementary and Alternative Medicine 12(S1) O55-O55. (2012) | yoga | RCT | 20 | Sleep quality | No difference | High |
| P02.156. Effects of a gentle yoga program on Restless Legs Syndrome (RLS) symptoms and related outcomes in women with RLS: a pilot study Kim E. Innes et al.. BMC Complementary and Alternative Medicine 12(S1) P212-P212. (2012) | gentle yoga | Quasi-Experimental | — | RLS symptoms overall | Inconclusive | High |
| Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial Mark J. Buchfuhrer et al.. BMC Neurology 23(1) 415. (2023) | tonic motor activation (tomac) | Quasi-Experimental | — | Proportion of participants completing step-down 1 with CGI-I score <=5 and actual opioid dose reduction >=20% | Inconclusive | High |
| Effect of dairy products fortified with vitamin d3 on restless legs syndrome in women with premenstrual syndrome, abdominal obesity and vitamin d deficiency: a pilot study Payam Sharifan et al.. BMC Women's Health 24(1) 434. (2024) | vitamin d3 | RCT | 141 | Restless Legs Syndrome score (overall, all participants) | No difference | Some Concerns |
| Therapeutic effects of magnesium and vitamin B6 in alleviating the symptoms of restless legs syndrome: a randomized controlled clinical trial Ali Jadidi et al.. BMC Complementary Medicine and Therapies 23(1) 1. (2022) | magnesium and vitamin b6 | RCT | 75 | Pittsburgh Sleep Quality Index (PSQI) Mean difference 1.68, p=0.70 | No difference | High |
| Ropinirole for restless legs syndrome Adler CH et al.. Neurology 62(8) 1405-1407. (2004) | ropinirole | Crossover | 22 | RLS Rating Scale score Mean difference -12.0 (-17.0–-6.30), p=0.00 | Favors treatment | Some Concerns |
| Efficacy of pergolide in treatment of restless legs syndrome Trenkwalder C. et al.. Neurology 62(8) 1391-1397. (2004) | pergolide | RCT | 100 | PLMS arousal index (periodic limb movements during sleep with arousals per hour of total sleep time) Mean difference -9.00, p=0.00 | Mixed | Some Concerns |
| Effective cabergoline treatment in idiopathic restless legs syndrome Stiasny-Kolster K. et al.. Neurology 63(12) 2272-2279. (2004) | cabergoline | RCT | 86 | RLS-6 Scale: Severity of RLS symptoms during the night Mean difference 2.45 (0.65–4.25), p=0.01 | Favors treatment | Some Concerns |
| Efficacy of cabergoline in restless legs syndrome Oertel WH et al.. Neurology 67(6) 1040-1046. (2006) | cabergoline | RCT | 43 | Periodic leg movements during sleep arousal index (PLMS-AI) Mean difference -13.1 (-21.3–-5.00), p=0.00 | Favors treatment | Some Concerns |
| Low-dose hydrocortisone in the evening modulates symptom severity in restless legs syndrome Hornyak M. et al.. Neurology 70(18) 1620-1622. (2008) | hydrocortisone | Crossover | 10 | Sensory leg discomfort (SLD) during Suggested Immobilization Test | Favors treatment | Some Concerns |
| Double-blind, placebo-controlled, pilot trial of botulinum toxin a in restless legs syndrome Fatta B. Nahab et al.. Neurology 71(12) 950-951. (2008) | botulinum toxin a | Crossover | 6 | Mean change in IRLS from baseline at 4 weeks postinjection Mean difference 4.00, p=0.06 | No difference | Some Concerns |
| Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS Kushida CA et al.. Neurology 72(5) 439-446. (2009) | xp13512 (gabapentin enacarbil) | RCT | 222 | IRLS total score - change from baseline Mean difference -6.00 (-7.90–-4.10), p=0.00 | Favors treatment | Some Concerns |
| Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome Axel Bauer et al.. Neurology 86(19) 1785-1793. (2016) | rotigotine | RCT | 81 | Total PLM-associated nocturnal SBP elevations Mean difference -160 (-213–-107), p=0.00 | Favors treatment | Low |
| Treatment of restless legs syndrome with pregabalin Garcia-Borreguero D. et al.. Neurology 74(23) 1897-1904. (2010) | pregabalin | RCT | 58 | International Restless Legs Scale (IRLS) total score Mean difference -5.26, p=0.00 | Favors treatment | Some Concerns |
| Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome Manconi M. et al.. Neurology 77(2) 110-117. (2011) | pramipexole | RCT | 45 | Visual Analogue Scale for RLS symptom severity (previous night leg/arm discomfort) Mean difference -4.10 | Favors treatment | High |
| 2012 Emerging Science Abstracts Neurology 79(11) 87-91. (2012) | pregabalin | RCT | 719 | International RLS Study Group Rating Scale (IRLS) score change from baseline Mean difference -4.50, p=0.00 | Favors treatment | Some Concerns |
| Pramipexole Alleviates Sensory and Motor Symptoms of Restless Legs Syndrome Jacques Montplaisir et al.. Neurology 51(1) 311-312. (1998) | pramipexole | Crossover | 10 | Periodic Leg Movement during Sleep (PLMS) index Mean difference -63.8, p=0.01 | Favors treatment | Some Concerns |
| Encouraging initial response of restless legs syndrome to pramipexole Philip M. Becker et al.. Neurology 51(4) 1221-1223. (1998) | pramipexole | Quasi-Experimental | — | Restless Legs Syndrome Rating Scale (RLSRS) total score Mean difference -9.20, p=0.00 | Favors treatment | High |
| Randomized, double-blind, placebo-controlled trial of pergolide in restless legs syndrome Christopher J. Earley et al.. Neurology 51(6) 1599-1602. (1998) | pergolide | RCT | 16 | PLMS per hour (periodic limb movements of sleep per hour) | No difference | Some Concerns |
| A randomized controlled study of pergolide in patients with restless legs syndrome Wetter TC et al.. Neurology 52(5) 944-944. (1999) | pergolide | Crossover | 30 | PLM index (periodic leg movements per hour of time in bed, during sleep and wakefulness) Mean difference -49.3, p=0.00 | Favors treatment | Some Concerns |
| Exercise Mediates The Association Between Sleep Quality And Restless Legs Syndrome Severity Melissa M. Aukerman et al.. Medicine & Science in Sports & Exercise 37(Supplement) S127. (2005) | aerobic and resistance training exercise | RCT | — | — | — | — |
| Management of Symptoms of Restless Legs Syndrome with Traction Straight Leg Raise: A Pilot Study Eric M. Dinkins et al.. Medicine & Science in Sports & Exercise 43(5) 903. (2011) | traction straight leg raise | RCT | — | — | — | High |
| Efficacy of Intravenous Iron Sucrose in Hemodialysis Patients with Restless Legs Syndrome (RLS): A Randomized, Placebo-Controlled Study Yinghui Deng et al.. Medical Science Monitor 23 1254-1260. (2017) | iron | RCT | 32 | IRLS score change from baseline Mean difference -6.57, p=0.00 | Favors treatment | High |
| Effect of Self-developed Ye’an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction Combined with Tramadol on TCM Symptom Scores and RLS Severity of patients with Restless Legs Syndrome Bowen Zhou et al.. Pakistan Journal of Medical Sciences 40(5) 1017-1021. (2024) | tramadol | RCT | 80 | International Restless Legs Scale (IRLS) score Mean difference -5.23, p=0.05 | No difference | High |
| Efficacy of neuromuscular electric stimulation versus aerobic exercise on uraemic restless legs syndrome Manal K. Youssef. International Journal of Therapy and Rehabilitation 26(10) 1-12. (2019) | neuromuscular electric stimulation | RCT | 60 | International Restless Legs Syndrome Study Group Rating Scale score Mean difference 4.60, p=0.00 | Favors treatment | High |
| Effect of Pramipexole on Cognitive Functions in Restless Legs Syndrome Minjik Kim et al.. Journal of Korean Sleep Research Society 11(1) 16-20. (2014) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Severity Scale (IRLS) Mean difference -14.9, p=0.00 | Favors treatment | High |
| Effect of governor moxibustion for restless legs syndrome of maintenance hemodialysis:a rando-mized controlled trial Gao Y. et al.. Zhongguo zhen jiu = Chinese acupuncture & moxibustion 36(6) 597-600. (2016) | governor moxibustion | RCT | 70 | International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score Mean difference -1.22, p=0.05 | No difference | Some Concerns |
| Haste makes waste: Decision making in patients with restless legs syndrome with and without augmentation Beatrice Heim et al.. PLOS ONE 12(4) e0174793. (2017) | dopaminergic agents | Quasi-Experimental | — | Number of beads drawn before making a decision (drawing behaviour) | Inconclusive | High |
| Randomized pilot trial for the efficacy of the MMF07 foot massager and heat therapy for restless legs syndrome Ariane Park et al.. PLOS ONE 15(4) e0230951. (2020) | foot massage and heat therapy | Factorial | 28 | International Restless Legs Severity Scale (IRLSS) Mean difference -9.00 (-16.3–-1.70), p=0.02 | Favors treatment | Some Concerns |
| Pneumatic Compression Devices Are an Effective Therapy for Restless Legs Syndrome Christopher J. Lettieri et al.. Chest 135(1) 74-80. (2009) | pneumatic compression devices | RCT | 35 | International Restless Legs Syndrome Study Group Severity Scale (IRLSSS) Mean difference -5.70, p=0.01 | Favors treatment | Some Concerns |
| Rifaximin Improves Restless Legs Syndrome Associated with Small Intestinal Bacterial Overgrowth Leonard Weinstock. American Journal of Gastroenterology 103 S107. (2008) | rifaximin | — | — | — | — | — |
| The Effect of Mindfulness-Based Stress Reduction on Restless Legs Syndrome in Hemodialysis Patients: A Randomized Clinical Trial Zahra Delshad et al.. Nurse Media Journal of Nursing 12(3) 316-324. (2022) | mindfulness-based stress reduction | RCT | 60 | Severity of Restless Legs Syndrome Mean difference 0.89 (-1.14–2.91), p=0.05 | No difference | Some Concerns |
| The effects of foot massage on hemodialysis patients’ sleep quality and restless leg syndrome: a comparison of lavender and sweet orange essential oil topical application Khodayar Oshvandi et al.. Journal of Complementary and Integrative Medicine 18(4) 843-850. (2021) | foot massage with lavender and sweet orange essential oils | RCT | — | — | — | High |
| Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome Feyza Ustabaş Kahraman et al.. Open Medicine 20(1) 20241125. (2025) | vitamin d | Quasi-Experimental | — | CSHQ Total Score | No difference | High |
| The effect of vibration on the severity of restless legs syndrome in hemodialysis patients Habibollah Hosseini et al.. Journal of Renal Injury Prevention 6(2) 113-116. (2016) | vibration therapy | Quasi-Experimental | — | Severity of restless legs syndrome symptoms Mean difference -6.17, p=0.00 | Inconclusive | High |
| The effects of vibration and massage on severity of symptoms of restless leg syndrome and sleep quality in hemodialysis patients; a randomized cross-over clinical trial Somayeh Azimpour et al.. Journal of Renal Injury Prevention 8(2) 106-111. (2018) | vibration and massage | Crossover | 80 | Severity of RLS symptoms Mean difference -2.68, p=0.00 | Favors treatment | High |
| Gabapentin for treatment of restless legs syndrome among hemodialysis patients; a pilot study Seyed Majid Mousavi Movahed et al.. Journal of Nephropharmacology 7(2) 104-109. (2018) | gabapentin | Crossover | 21 | RLS symptom severity score (standardized questionnaire) Mean difference 0.35 | Inconclusive | Some Concerns |
| Effect of intravenous vitamin C supplementation on the quality of sleep, itching and restless leg syndrome in patients undergoing hemodialysis; A double-blind randomized clinical trial Shahdak Dadashpour et al.. Journal of Nephropharmacology 7(2) 131-136. (2018) | intravenous vitamin c | RCT | 90 | Pittsburgh Sleep Quality Index (PSQI) total score | Favors treatment | High |
| Effect of transcutaneous electrical nerve stimulation with stretching and exercises in restless leg syndrome among pregnant women Augustina, S Jenifer et al.. Obstetrics & Gynecology International Journal 11(2). (2020) | transcutaneous electrical nerve stimulation with stretching | Quasi-Experimental | 30 | Numeric Pain Rating Scale (NPRS) Mean difference -2.67, p=0.00 | Favors treatment | High |
| Use of Potassium Citrate in Restless Leg Syndrome (RLS) Choudhury Mizanur Rouf. Pharmacy & Pharmacology International Journal 4(4). (2016) | potassium citrate | Quasi-Experimental | — | RLS severity level (Visual Analogue Scale) | Inconclusive | High |
| The effect of compression stockings on the complaints well-being and sleep quality of pregnant women with restless legs syndrome: a randomized controlled study Özlem Kaplan et al.. Revista da Associação Médica Brasileira 70(7) e20240145. (2024) | compression stockings | RCT | 70 | Restless Legs Syndrome Severity Rating Scale (IRLSSG) Mean difference 0.28, p=0.84 | No difference | Some Concerns |
| Effect of aerobic exercise and yogasana programme on fatigue and stress in peripheral neuropathy patients with restless leg syndrome T. Suresh Kumar et al.. International Journal of Physiotherapy and Research 5(4) 2220-2224. (2017) | aerobic exercise and yogasana | Quasi-Experimental | 60 | Perceived Stress Scale score Mean difference 0.53 | Favors treatment | High |
| The Effect of Massage With Lavender Oil on Restless Leg Syndrome in Hemodialysis Patients: A Randomized Controlled Trial Sayyed Hossein Hashemi et al.. Nursing and Midwifery Studies 4(4) e29617. (2015) | massage with lavender oil | RCT | 70 | Restless Leg Syndrome severity score Mean difference -0.49, p=0.76 | No difference | High |
| Effectiveness of muscle stretching exercise on restless leg syndrome among patients undergoing haemodialysis Jasvinder Kaur et al.. International Journal of Research in Medical Sciences 2164-2169. (2016) | muscle stretching exercise | Quasi-Experimental | 86 | RLS symptom severity score (Restless Legs Syndrome Rating Scale) Mean difference -0.54, p=0.60 | No difference | High |
| Clinical aspects and differentiated therapy strategies for idiopathic form of restless legs syndrome Umida G. Yodgorova et al.. The Bulletin of Contemporary Clinical Medicine 18(2) 24-28. (2025) | iron, vitamin d, vitamin b12, folic acid, magnesium, calcium supplementation | Quasi-Experimental | 51 | Plasma 25(OH)D concentration (vitamin D level) Mean difference 17.8, p=0.00 | Favors treatment | High |
| Change of International Restless Legs Syndrome Study Group Rating Scale subscales with treatment and placebo: a pilot study Ulrike Mitchell et al.. Journal of Parkinsonism and Restless Legs Syndrome 27. (2014) | unspecified non-pharmaceutical treatment | Quasi-Experimental | 58 | IRLS Total Score Mean difference -7.20, p=0.00 | Favors treatment | High |
| Vibration and skin blood flow changes in subjects with restless legs syndrome Ulrike Mitchell et al.. Journal of Parkinsonism and Restless Legs Syndrome 9. (2014) | whole body vibration | — | — | — | — | — |
| Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome Yanan Zhang et al.. Nature and Science of Sleep Volume 16 431-443. (2024) | pramipexole and gabapentin | Quasi-Experimental | — | Phase Difference (dynamic cerebral autoregulation) Mean difference -13.0, p=0.00 | Inconclusive | High |
| Dose Response of Gabapentin Enacarbil versus Placebo in Subjects with Moderate-to-Severe Primary Restless Legs Syndrome Susan A. VanMeter et al.. CNS Drugs 26(9) 773-780. (2012) | gabapentin enacarbil (horizant) | RCT | 760 | Change from baseline in IRLS total score Mean difference -4.00, p=0.00 | Favors treatment | Some Concerns |
| Treatment of Japanese Restless Legs Syndrome Patients with Cabergoline: An Open Clinical Preliminary Trial Hitoshi Aizawa et al.. Internal Medicine 45(7) 453-455. (2006) | cabergoline | Quasi-Experimental | — | IRLSSG Rating Scale Version 2.2 total score Mean difference -14.8, p=0.03 | Favors treatment | High |
| 10.2174/0118746136268741240328062217 | neurofeedback | RCT | 30 | Subjective sleep quality (Pittsburgh Sleep Quality Index component) | No difference | High |
| Comparison of the effect of cold dialysate versus stretching exercises on severity of restless legs syndrome in patients undergoing hemodialysis: A randomized controlled trial Azam Zirak Aliabadi et al.. Evidence Based Care Journal 10(3) 14-22. (2020) | cold dialysate and stretching exercises | RCT | 44 | Severity of restless legs syndrome Mean difference 3.60 | No difference | Some Concerns |
| Effects of warm and cold footbath on sleep quality in pregnant women with restless legs syndrome جعفریمنش, هادی et al.. Iranian Journal of Obstetrics, Gynecology and Infertility 26(6) 51-60. (2020) | warm and cold water footbath | RCT | 80 | Pittsburgh Sleep Quality Index total score Mean difference 0.92, p=0.07 | No difference | Some Concerns |
| The Effect of Massage and Biochemical Oxidative Stress Determinants in Hemodialysis Patients with Restless Leg Syndrome in Turkish People Aysel Güven et al.. International Journal of Computational and Experimental Science and Engineering 11(3). (2025) | massage | Quasi-Experimental | 42 | Restless Legs Syndrome severity (IRLS scale) | Inconclusive | High |
| The effect of hot water application in pregnant women with restless legs syndrome: a randomised controlled study Cossu G. et al.. Authorea, Inc. 2(2) V1. (2021) | hot water immersion | RCT | — | Restless Legs Syndrome Severity Grading Scale | No difference | High |
| Effects of progressive muscle relaxation exercises and relaxation music on the severity of restless legs syndrome and sleep quality during pregnancy: A randomized controlled trial Cossu G. et al.. Authorea, Inc. 2(2) V1. (2023) | progressive muscle relaxation exercises | RCT | 67 | Severity of Restless Legs Syndrome | Inconclusive | High |
| Pengaruh Latihan Kekuatan terhadap Restless Legs Syndrome Pasien Hemodialisis Anggriyana Tri Widianti et al.. Jurnal Keperawatan Padjadjaran 5(1). (2017) | strength training (latihan kekuatan) | Quasi-Experimental | 32 | RLS scale (IRLS Scale) Mean difference -3.16, p=0.04 | Favors treatment | High |
| The effect of intradialysis stretching exercise on the scale of restless leg syndrome Ahyar Nur et al.. Journal of Islamic Nursing 3(2) 16. (2018) | stretching exercise | Quasi-Experimental | 20 | Restless Legs Syndrome severity scale Mean difference 0.30, p=0.00 | No difference | High |
| Clinical Study on Treatment of 39 Cases of Uremic Restless Leg Syndrome by Rouxiujiang Decoction Combined with Acupoint Massage Hongxia Xie. 2018 International Conference on Biomedical Engineering, Machinery and Earth Science (BEMES 2018). (2018) | rouxiujiang decoction | RCT | 78 | RLS severity score Mean difference -0.05, p=0.82 | No difference | High |
| The Effect of Selected Core Stability Exercises on Restless Legs Syndrome and Quality of Life in the Elderly Undergoing Hemodialysis Mehrdad Bastani et al.. Qom Univ Med Sci J 12(8) 48-58. (2018) | core stability exercises | Quasi-Experimental | 30 | Restless legs syndrome severity score Mean difference -5.70, p=0.00 | Favors treatment | High |
| Actigraphy as a marker for therapy efficacy in patients with restless legs syndrome against the background of diabetic polyneuropathy N. P. Tkachuk et al.. Ukrainian Neurological Journal 0(3—4) 46-51. (2018) | pramipexole | RCT | 43 | Periodic Limb Movement Index (PLMI) during sleep measured by actigraphy Mean difference -2.08, p=0.05 | No difference | High |
| Pilot Trial of OnabotulinumtoxinA (Botox) in Moderate to Severe Restless Legs Syndrome Pinky Agarwal et al.. International Journal of Neuroscience 121(11) 622-625. (2011) | onabotulinum toxin a | Quasi-Experimental | — | International Restless Legs Syndrome Scale (IRLSS) Mean difference -5.75 (-10.8–-0.67), p=0.03 | Inconclusive | High |
| Comparison of two infrared devices in their effectiveness in reducing symptoms associated with RLS Mitchell UH et al.. Physiotherapy Theory and Practice 27(5) 352-359. (2011) | near-infrared light | RCT | 26 | International Restless Legs Syndrome Study Group rating scale (IRLS) score Mean difference 2.30, p=0.31 | No difference | Some Concerns |
| Restless legs syndrome and near-infrared light: An alternative treatment option Mitchell UH et al.. Physiotherapy Theory and Practice 27(5) 345-351. (2011) | near-infrared light | RCT | 34 | International RLS Rating Scale (IRLS) score Mean difference -2.20, p=0.09 | No difference | Some Concerns |
| Using near infrared light to manage symptoms associated with restless legs syndrome Guffey JS et al.. Physiotherapy Theory and Practice 32(1) 34-44. (2016) | near-infrared light | Quasi-Experimental | — | International Restless Legs Syndrome Rating Scale (IRLSRS) Mean difference 9.70 (6.20–13.2), p=0.00 | Inconclusive | High |
| Effect of Near-Infrared Light Therapy Based on Acupoints on the Severity of Restless Legs Syndrome in Patients Undergoing Hemodialysis: A Single-Blind, Randomized Controlled Trial Mohammad Mehdi Mohammadi et al.. Clinical Medicine & Research 16(1-2) 1-8. (2018) | near-infrared light therapy | RCT | 60 | RLS severity score Mean difference -0.40, p=0.50 | No difference | Some Concerns |
| Exercise and Restless Legs Syndrome: A Randomized Controlled Trial Aukerman MM et al.. The Journal of the American Board of Family Medicine 19(5) 487-493. (2006) | aerobic exercise and resistance training | RCT | 41 | International RLS Study Group (IRLSSG) severity scale total score Mean difference -1.90, p=0.46 | No difference | Some Concerns |
| Bupropion and Restless Legs Syndrome: A Randomized Controlled Trial Bayard M. et al.. The Journal of the American Board of Family Medicine 24(4) 422-428. (2011) | bupropion | RCT | 60 | IRLSSG severity score Mean difference -4.40, p=0.03 | Favors treatment | Some Concerns |
| Novel Exercises for Restless Legs Syndrome: A Randomized, Controlled Trial Eloise G. Harrison et al.. The Journal of the American Board of Family
Medicine 31(5) 783-794. (2018) | tension and trauma release exercises | RCT | 18 | International Restless Legs Syndrome Rating Scale (IRLS) score Mean difference -2.80 (-8.90–3.40), p=0.40 | No difference | Some Concerns |
| The Effect of Heat Therapy on the Severity of Restless Legs Syndrome and Sleep Quality in the Elderly Hojjat Azizkhani et al.. Complementary Medicine Journal 12(2) 202-213. (2022) | heat therapy | Quasi-Experimental | 88 | Severity of Restless Legs Syndrome Mean difference 0.20, p=0.32 | No difference | High |
| 10.33588/rn.2909.99317 | ropinirole | Quasi-Experimental | 5 | Sleep efficiency Mean difference 20.2, p=0.01 | Favors treatment | High |
| Effect of Intradialytic Resistance Exercise on Restless Legs Syndrome Among Hemodialysis Patients: A Pilot Randomized Controlled Trial Achmad Fauzi et al.. Jurnal Keperawatan Komprehensif (Comprehensive Nursing Journal) 12(1) 1-8. (2026) | intradialytic resistance exercise | RCT | 42 | International RLS Severity Scale (IRLS) total score Mean difference -0.60 (-2.30–1.10), p=0.52 | No difference | Some Concerns |
| The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients Hyoeun Bae et al.. Frontiers in Neurology 12 786408. (2021) | pregabalin | Quasi-Experimental | — | International Restless Legs Scale (IRLS) score Mean difference -5.57, p=0.00 | Mixed | High |
| Transcutaneous Spinal Cord Direct-Current Stimulation Modulates Functional Activity and Integration in Idiopathic Restless Legs Syndrome Min Zeng et al.. Frontiers in Neuroscience 14 873. (2020) | transcutaneous spinal cord direct-current stimulation (tsdcs) | RCT | 30 | International RLS Rating Scale (IRLS-RS) Mean difference -8.40 | Inconclusive | High |
| Aromatherapy Massage vs. Foot Reflexology on the Severity of Restless Legs Syndrome in Female Patients Undergoing Hemodialysis Mahbobeh Ghasemi et al.. Geriatrics 6(4) 99. (2021) | aromatherapy massage | RCT | 105 | Severity of Restless Legs Syndrome Mean difference -2.71, p=0.01 | Favors treatment | Some Concerns |
| The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT Susanne Macher et al.. Nutrients 12(5) 1313. (2020) | iron | RCT | 176 | Restless Legs Syndrome diagnosis (prevalence) | No difference | Some Concerns |
| Botulinum Toxin in Restless Legs Syndrome—A Randomized Double-Blind Placebo-Controlled Crossover Study Shivam Om Mittal et al.. Toxins 10(10) 401. (2018) | incobotulinumtoxin a | Crossover | 24 | International Restless Legs Syndrome Score (IRLS) — categorical improvement from severe to mild/moderate | Favors treatment | Some Concerns |
| Comparison of the effects of pramipexole and gabapentin on the treatment of restless leg syndrome in end-stage chronic renal failure patients undergoing hemodialysis Sepideh Hajian et al.. Journal of Nephropathology 9(3) e25-e25. (2020) | pramipexole | RCT | 60 | RLS severity score (IRLSSG) Mean difference 0.10 | Favors treatment | High |
| Pengaruh Latihan Peregangan Intradialitik terhadap Restless Legs Syndrome pada Pasien Hemodialisis Rogayah et al.. Jurnal Antara Keperawatan 482-486. (2022) | intradialytic stretching exercise | Quasi-Experimental | 40 | RLS symptom severity (IRLSSG score) Mean difference -6.30 | Inconclusive | High |
| El efecto de la relajación muscular progresiva en la reducción del síndrome de las piernas inquietas entre los pacientes sometidos a hemodiálisis en una unidad periférica en Indonesia Tria Firza Kumala et al.. Enfermería Nefrológica 24(4) 409-415. (2021) | progressive muscle relaxation | Quasi-Experimental | 24 | Restless Legs Syndrome severity score Mean difference -6.08 | Favors treatment | High |
| Comparison of the Effect of Reflexology and Swedish Massage on Restless Legs Syndrome and Sleep Quality in Patients Undergoing Hemodialysis: a Randomized Clinical Trial Ghanbari A. et al.. International Journal of Therapeutic Massage & Bodywork: Research, Education, & Practice 15(2) 1-13. (2022) | foot reflexology and swedish massage | RCT | 90 | Restless Leg Syndrome severity score Mean difference -0.23, p=0.23 | No difference | Some Concerns |
| Nutritional Supplements and its Effect on Quality of Life and Sleep H.. American Medical Journal 2(2) 104-110. (2011) | vitamin b12 injections | Quasi-Experimental | 34 | Insomnia improvement (percentage of subjects improved) | Inconclusive | High |
| Clinical Efficacy of Heel Vessel Catgut Embedding in the Treatment of Primary Restless Legs Syndrome Hui Shi et al.. International Journal of Pharmacology 21(1) 131-137. (2025) | heel vessel catgut embedding | RCT | 42 | International Restless Legs Syndrome Scale (IRLS) score Mean difference -0.33, p=0.05 | No difference | High |
| Abnormal Sleep Delta Rhythm and Interregional Phase Synchrony in Patients with Restless Legs Syndrome and Their Reversal by Dopamine Agonist Treatment Jeong Woo Choi et al.. Journal of Clinical Neurology 13(4) 340. (2017) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Severity Scale (IRLS) score Mean difference -16.4, p=0.03 | Favors treatment | High |
| Efficacy and Safety of Pregabalin for Restless Legs Syndrome in Korean Adults: A Randomized, Double-Blind, Placebo-Controlled Trial Jun-Sang Sunwoo et al.. Journal of Clinical Neurology 21(4) 325. (2025) | pregabalin | RCT | 78 | International Restless Legs Scale (IRLS) score change from baseline Mean difference 1.50, p=0.42 | No difference | Some Concerns |
| Holter electrocargiogram recording of periodic limbs movements in uremic restless legs syndrome: Application for diagnosis and evaluation of drug effects Hidemaro Sato et al.. Nihon Toseki Igakkai Zasshi 36(3) 207-215. (2003) | pergolide mesylate | Quasi-Experimental | — | PLM frequency (periodic limb movements per 30 minutes) — Holter ECG recording Mean difference -25.4, p=0.05 | No difference | High |
| Examination of clinical effectiveness of Pramipexole for restless legs syndrome in hemodialysis patients Takeshi Wakikawa et al.. Nihon Toseki Igakkai Zasshi 44(12) 1155-1161. (2011) | pramipexole | Quasi-Experimental | — | International Restless Legs Syndrome Rating Scale (IRLS) total score Mean difference -10.3, p=0.00 | Inconclusive | High |
| Ropinirole in the Treatment of Patients With Restless Legs Syndrome: A US-Based Randomized, Double-Blind, Placebo-Controlled Clinical Trial Richard K. Bogan et al.. Mayo Clinic Proceedings 81(1) 17-27. (2006) | ropinirole | RCT | 381 | International Restless Legs Scale (IRLS) total score Mean difference -2.20 (-3.60–-0.70), p=0.00 | Favors treatment | Some Concerns |
| Repetitive Transcranial Magnetic Stimulation for the Treatment of Restless Legs Syndrome Yi-Cong Lin et al.. Chinese Medical Journal 128(13) 1728-1731. (2015) | repetitive transcranial magnetic stimulation (rtms) | Quasi-Experimental | — | International RLS Rating Scale (IRLS-RS) Mean difference -12.7, p=0.00 | Inconclusive | High |
| A double-blind, randomized, controlled trial to compare the efficacy and tolerability of fixed doses of ropinirole, bupropion, and iron in treatment of restless legs syndrome (Willis–Ekbom disease) Kirti Vishwakarma et al.. Annals of Indian Academy of Neurology 19(4) 472-477. (2016) | ropinirole | RCT | 90 | International Restless Legs Scale (IRLS) severity score | Mixed | Some Concerns |
| The effects of two methods of reflexology and stretching exercises on the severity of restless leg syndrome among hemodialysis patients Nahid Shahgholian et al.. Iranian Journal of Nursing and Midwifery Research 21(3) 219. (2016) | reflexology and stretching exercises | RCT | 90 | Restless leg syndrome severity score Mean difference -15.9, p=0.00 | Favors treatment | Some Concerns |
| The Effect of the cool dialysate on the restless leg syndrome in hemodialysis patients: Randomized triple-blind clinical trial Mostafa Rad et al.. Iranian Journal of Nursing and Midwifery Research 24(3) 200. (2019) | cool dialysate | RCT | 63 | RLS severity score Mean difference 3.06, p=0.05 | No difference | Some Concerns |
| A prospective, randomized, open-label study comparing the efficacy and safety of clonazepam versus nortriptyline on quality of life in 40+ years old women presenting with restless leg syndrome Annil Mahajan et al.. Journal of Mid-life Health 9(3) 135. (2018) | clonazepam | RCT | 120 | Restless Legs Syndrome Quality of Life Score Mean difference 0.23, p=0.94 | No difference | High |
| Comparative efficacy and safety of clonazepam versus nortriptyline in restless leg syndrome among forty plus women: A prospective, open-label randomized study Annil Mahajan et al.. Journal of Mid-life Health 10(4) 197. (2019) | clonazepam | RCT | 120 | International Restless Leg Syndrome Scale (IRLSS) total score Mean difference -1.46, p=0.36 | Mixed | High |
| Biotin Deficiency as a Target for Treating Restless Legs Syndrome in Chronic Dialysis Patients Heidi Moretti. Journal of Nephrology & Therapeutics 02(06). (2012) | biotin | RCT | 37 | International Restless Legs Syndrome Study Group (IRLS) Rating Scale Score | No difference | High |
| Pramipexole versus dual release levodopa in restless legs syndrome: a double blind, randomised, cross-over trial Bassetti CL et al.. Swiss Medical Weekly 141(4748) w13274. (2011) | pramipexole | Crossover | 67 | Periodic Limb Movement Index (PLM index, PLMI) Mean difference -3.80, p=0.00 | Favors treatment | Some Concerns |
| Comparison of aerobic and strength training exercises for restless leg syndrome, sleep quality, and daytime sleepiness in patients with diabetes mellitus: a randomized clinical trial Fizah Mahnoor Khan et al.. Advances in Rehabilitation 39(4) 67-81. (2025) | aerobic and resistance training | RCT | 42 | International Restless Legs Syndrome Rating Scale total score Mean difference 5.00, p=0.23 | No difference | Some Concerns |
| Comparison of lacosamide versus levodopa in the treatment of restless legs syndrome in hemodialysis patients Muhammad Ameem et al.. Pakistan Postgraduate Medical Journal 34(04) 192-196. (2023) | lacosamide | — | — | — | — | — |
| Effects of Alternative Therapies on Pain, Anxiety, Quality of Sleep, Activities of Daily Livings (ADLS) And Quality of Life in Patients with Restless Legs Syndrome (RLS): A Randomized Controlled Trial Antara Bishnu, Priyanka Sethi. Journal of Chemical Health Risks. (2025) | yoga and physiotherapy | RCT | 42 | Pain severity (Visual Analog Scale) Mean difference -2.17, p=0.00 | Mixed | High |
| Effect of stretching exercises versus thermotherapy on restless legs syndrome symptoms, pain, and quality of sleep among pregnant women Abeer Hassan Shamekh et al.. International journal of health sciences 11204-11220. (2022) | stretching exercises | Quasi-Experimental | 60 | Total RLS Symptoms Severity Score Mean difference -4.43, p=0.00 | Favors treatment | High |
| Effectiveness of a Self‑Stretching Exercise Program on Restless Leg Symptoms in Patients with Type 2 Diabetes Mellitus: A Pre-Post Intervention Analysis Nasir Mehmood et al.. Pakistan BioMedical Journal 40-45. (2026) | self-stretching exercise | Quasi-Experimental | — | RLS-DI Sum Score | Inconclusive | High |
| The Effect of Wet Cupping Therapy on Patients' Symptom Level and Sleep Quality on Restless Leg Syndrome Gülsüm Yurttutan et al.. Ankara Medical Journal 20(4) 904-916. (2020) | wet cupping therapy | Quasi-Experimental | 16 | RLS Severity Scale Total Score (HBSSS / IRLSSG Severity Scale) Mean difference -3.25, p=0.60 | No difference | High |
| Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms Jonathan D. Charlesworth et al.. Journal of Clinical Sleep Medicine 19(7) 1199-1209. (2023) | noninvasive peroneal nerve stimulation | Crossover | 43 | International RLS Study Group Rating Scale (IRLS) total score Mean difference -4.50 | Favors treatment | Some Concerns |
| Magnesium citrate monotherapy improves restless legs syndrome symptoms and multiple suggested immobilization test scores in an open-label pilot study Sasikanth Gorantla et al.. Journal of Clinical Sleep Medicine 20(8) 1357-1361. (2024) | magnesium citrate | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLS) Mean difference 6.67 (2.33–11.0), p=0.01 | Inconclusive | High |
| Effect of Sensory Stimuli on Restless Legs Syndrome: A Randomized Crossover Study Anouk D. Rozeman et al.. Journal of Clinical Sleep Medicine 10(8) 893-896. (2014) | sensory stimulation | Crossover | 21 | Leg discomfort - Visual Analogue Scale at baseline (start of SIT) | No difference | Some Concerns |
| Pramipexole Alters Thermoregulation in Restless Legs Syndrome Aaro V. Salminen et al.. Journal of Clinical Sleep Medicine 10(12) 1325-1329. (2014) | pramipexole | Crossover | 29 | Subjective discomfort during suggested immobilization test (SIT) Mean difference 4.10, p=0.00 | Favors treatment | High |
| Decreased Symptoms without Augmented Skin Blood Flow in Subjects with RLS/WED after Vibration Treatment Ulrike H. Mitchell et al.. Journal of Clinical Sleep Medicine 12(7) 947-952. (2016) | whole body vibration | Crossover | 13 | RLS symptom severity (IRLS) | Favors treatment | Some Concerns |
| Effects of a 12-week yoga versus a 12-week educational film intervention on symptoms of restless legs syndrome and related outcomes: an exploratory randomized controlled trial Kim E. Innes et al.. Journal of Clinical Sleep Medicine 16(1) 107-119. (2020) | yoga | RCT | 41 | International RLS Study Group Scale (IRLS) total score Mean difference -5.24, p=0.01 | Favors treatment | Some Concerns |
| Noninvasive neuromodulation reduces symptoms of restless legs syndrome Mark J. Buchfuhrer et al.. Journal of Clinical Sleep Medicine 17(8) 1685-1694. (2021) | noninvasive peripheral nerve stimulation | Crossover | 43 | International RLS Study Group Rating Scale (IRLS) score Mean difference -3.43, p=0.00 | Favors treatment | Some Concerns |
| 10.5665/sleep/31.9.1229 | pramipexole | RCT | 43 | PLMS Index (periodic leg movements during sleep per hour of sleep) Mean difference -36.8, p=0.00 | Favors treatment | Some Concerns |
| Pregabalin Versus Pramipexole: Effects on Sleep Disturbance in Restless Legs Syndrome Diego Garcia-Borreguero et al.. Sleep 37(4) 635-643. (2014) | pregabalin | Crossover | 85 | Wake After Sleep Onset (WASO) by polysomnography Mean difference -27.1 (-35.8–-18.4), p=0.00 | Favors treatment | Some Concerns |
| Clinical features of idiopathic restless legs syndrome in Japanese patients Akito Kume et al.. Rinsho Shinkeigaku 50(6) 385-392. (2010) | dopaminergic agents | Quasi-Experimental | — | Response to dopaminergic treatment (improvement) | Inconclusive | High |
| The Effect of Stretching Exercises on Severity of Restless Legs Syndrome in Patients on Hemodialysis Mansooreh Aliasgharpour et al.. Asian Journal of Sports Medicine 7(2) e31001. (2016) | stretching exercises | RCT | 36 | Severity of restless legs syndrome symptoms Mean difference -0.06, p=0.97 | No difference | High |
| Effect of Pramipexole on Headache Relief in Patients with Concomitant Migraine and Restless Legs Syndrome; A Randomized, Controlled, Clinical Trial Shahram Rafie et al.. Jundishapur Journal of Natural Pharmaceutical Products 14(3). (2019) | pramipexole | RCT | 30 | MIDAS Score (Migraine Disability Assessment Score) Mean difference -1.46, p=0.09 | No difference | Some Concerns |
| Effectiveness Of Buerger Allen Exercise Among Pregnant Women With Restless Leg Syndrome In A Selected Hospital Banke, Nepal Srijana Sapkota. DIROSAT: Journal of Education, Social Sciences & Humanities 1(4) 159-166. (2023) | buerger allen exercise | Quasi-Experimental | 60 | RLS severity rating score Mean difference -4.03 | Favors treatment | High |
| Saint John's wort, an herbal inducer of the cytochrome P4503A4 isoform, may alleviate symptoms of Willis-Ekbom's disease José Carlos Pereira et al.. Clinics 68(4) 469-474. (2013) | saint john's wort | Quasi-Experimental | — | Willis-Ekbom Disease severity score (IRLSSG rating scale) | Favors treatment | High |
| Investigating The Effect of Transcutaneous Electrical Nerve Stimulation on The Severity of Restless Legs Syndrome in Hemodialysis Patients Abolfazl Kalmishi et al.. Scientific Journal of Kurdistan University of Medical Sciences 29(4) 49-58. (2024) | transcutaneous electrical nerve stimulation (tens) | RCT | 60 | Restless legs syndrome severity Mean difference -0.37, p=0.69 | No difference | High |
| Treatment of Willis-Ekbom Disease (Restless Leg Syndrome); The Efficacy of Mulligan's Traction Straight Leg Raise among Paramedical Professionals. Usman Iqbal Janjua et al.. Journal of Health and Rehabilitation Research 3(2) 1052-1057. (2023) | mulligan's traction straight leg raise | RCT | 38 | RLS Rating Scale Mean difference -0.90, p=0.56 | No difference | High |
| Effects of Stretching Exercises and Myofascial Pain Release on Pain and Sleep Quality in Antenatal Restless Leg Syndrome Hafiza Iqra Rubab et al.. Journal of Health and Rehabilitation Research 4(2) 194-199. (2024) | stretching exercises | RCT | 22 | Numeric Pain Rating Scale (NPRS) | Inconclusive | High |
| Efficacy Of Interval Aerobic Training Versus Laser Puncture Therapy On The Severity Of Restless Leg Syndrome In Chronic Obstructive Lung Patients Ola Mohamed Elgohary, Elgohary. International Journal of Environmental Sciences 6578-6588. (2025) | interval aerobic training | RCT | 60 | Restless Legs Syndrome Rating Scale (IRLS) Mean difference -2.27, p=0.03 | Favors treatment | High |
| Cortical spectral rebalancing underlies pregabalin’s efficacy in restless legs syndrome Aref Zabeh et al.. bioRxiv (Cold Spring Harbor Laboratory). (2025) | pregabalin | RCT | 103 | RLS severity score (IRLSSG rating scale) — absolute score at baseline | Favors treatment | Some Concerns |
| Effektivitas aerobic exercise dan stretching exercise intradialytic terhadap penurunan restless leg syndrome pada pasien gagal ginjal kronik dengan hemodialisis Achmad Fauzi et al.. Jurnal Keperawatan PPNI Jawa Barat 1(1). (2023) | aerobic exercise and stretching exercise | Quasi-Experimental | 80 | Restless Legs Syndrome severity level (categorical score) Mean difference -0.63 | Favors treatment | High |
| The Study on Effect of Korean Medical Treatment for Patients with Restless Legs Syndrome Yu-Jin Lee et al.. Journal of Oriental Neuropsychiatry 26(4) 357-364. (2015) | korean medicine (herbal medication, acupuncture, oriental psychotherapy) | Quasi-Experimental | — | International Restless Legs Syndrome Study Group Rating Scale (IRLS) Mean difference -5.08, p=0.06 | No difference | High |
| Targeted Pressure on Abductor Hallucis and Flexor Hallucis Brevis Muscles to Manage Moderate to Severe Primary Restless Legs Syndrome Phyllis J. Kuhn et al.. Journal of Osteopathic Medicine 116(7) 440-450. (2016) | targeted pressure device (abductor hallucis and flexor hallucis brevis muscles) | Quasi-Experimental | — | IRLSSG Rating Scale total score Mean difference 5.22, p=0.00 | Inconclusive | High |