Table 1
Studies included.
| NAME OF THE MEDICATION | AUTHOR | STUDY DESIGN | SAMPLE SIZE ENROLLED (TREATED) | DOSAGES | RESULTS | SIDE/ADVERSE EFFECTS REPORTED IN THE STUDY |
|---|---|---|---|---|---|---|
| 3.1. Reduction in Adrenergic transmission | ||||||
| Clonidine | Handwerker et al [21] | • case series | 3 | 0.1 mg twice a day; 0.1 mg at bedtime; 0.3 mg at night | 3/3 completely relieved | |
| Bastani et al [23] | • case series | 6 | 0.1 mg twice a day, and one needed this dose three times a day for optimal response | 6/6 patients had moderate to marked improvement in their RLS symptoms | 3/6 fatigue, drowsiness, dry mouth | |
| Bamford et al [24] | • open-label | 7 | initiated at 0.1 mg/night and increased to 0.2 mg/night the following week | provoking RLS | 7/7 insomnia; 2/7 exacerbation RLS; 2/7 intolerable headaches, hypotension | |
| Ausserwinkler et al [19]* | • double-blind • parallel • placebo-controlled | 20 (10 on drug and 10 on placebo) | 0.075 mg bid twice daily | 8/10 patients complete relief; 1 patient striking relief; 1 patient unchanged; 1 placebo subject mild alleviation | ||
| Wagner et al [25] | • double-blind • crossover • randomized • placebo-controlled | 11 (5 on drug and 5 on placebo); 1 drop-out | a mean dose of 0.5 mg and maximum dose of 1.0 mg/day; | improved leg sensations, motor restlessness, daytime fatigue; quicker sleep onset; 7/10 patients more effect than placebo; 4/7 continued use after the study | decrease in REM sleep and sleep latency; increase in REM latency; 8/10 dry mouth, 6/10 decreased cognition, 5/10 sleepiness after dose, 4/10 constipation, 2/10 decreased libido and 2/10 headache | |
| Zoe et al [26] | • case report | 1 | 0.9 mg/d | mild hypertension normalized | a dry mouth | |
| Prescriber guidelines: used cautiously in older individuals with accompanying cardiovascular disease [30] | ||||||
| 3.2. Adenosine Transporter Inhibitor | ||||||
| Dipyridamole | Garcia-Borreguero et al [33] | • open-label • uncontrolled | 15 (13 completed study) | began treatment with 100 mg dipyridamole (with up-titration to 400 mg if necessary) at 8:00 p.m.; mean effective dose: 281.8 ± 57.5 mg/day | 6/13 full responders; 4/13 partial responders; improved PLMS index and sleep variables; improved per IRLS scale score, CGI and mSIT | abdominal cramps, diarrhea, dizziness, and flushing |
| Garcia-Borreguero et al [34] | • double-blind • crossover • randomized • placebo-controlled | 29 (14 on drug and 14 on placebo) | up-titration to a maximum of 300 mg at 9:00 PM [34] | improved per IRLS score, CGI, Medical Outcomes Study Sleep Scale and mSIT scores; Sleep variables and PLMS | mild side effects: abdominal distension, dizziness, diarrhea, and asthenia | |
| Prescriber guidelines: caution must be exercised in the administration of this agent, particularly in those who are receiving other antiplatelet therapy [35, 36] | ||||||
| 3.3. Glutamate | ||||||
| 3.3.1 AMPA Receptor Antagonist | ||||||
| Perampanel | Garcia-Borreguero et al [38] | • open-label • uncontrolled | 22 (20 completed study) | 2 mg- 4 mg at 19:00; mean dose: 3.8 ± 1.2 mg/day | improved IRLS scale score, mSIT, PLMS index; 12/20 full responders; 4/20 partial responders | 6/20 dizziness, 2/20 somnolence, 1/20 headache and 5/20 irritability; 1 patient discontinued because of irritability; 1 patient discontinued because of lack of efficacy |
| Prescriber guidelines: serious psychiatric side effects are common [39] | ||||||
| 3.3.2. NMDA Receptor Antagonists | ||||||
| Amantadine | Evidente et al [40] | • open-label • uncontrolled | 21 | 100 mg- 300 mg/day; mean dose: 227 mg/day | 11/21 mild subjective improvement; 6/21 strong subjective improvement RLS rating scale | 3/21 drowsiness, 2/21 fatigue, 2/21 insomnia, 1/21 dry mouth, 1/21 leg edema and 1/21 weight loss; 1 patient discontinued because of leg edema; 1 patient discontinued because of fatigue, drowsiness and weight loss |
| Prescriber guidelines: possibility of daytime sleep attacks, impulse control disorders and hallucinations [41] | ||||||
| Ketamine | Kapur et al [42] | • case series | 2 | 30–40 mg bid mixed with 50 ml water twice a day given orally | significant improvement in sleep and RLS symptoms | |
| Prescriber guidelines: possibility of cardiac arrhythmia, hypotension, dependence, respiratory depression, and hallucination[43] | ||||||
| 3.4 Anticonvulsants Other Than Gabapentin And Pregabalin | ||||||
| Carbamazepine | Lundvall et al [44] | • double-blind • crossover • randomized • placebo-controlled | 6 (with 2 only for three weeks on placebo) | 200 mg; 1 tablet in the morning and 2 tablets in the evening | 3/6 were subjective responders; drop of 21% severity score compared placebo value; 3 patients continued after study | 1 patient experienced mild gastritis; 1 subject experienced sweating, dry mouth and vomiting |
| Telstad et al [45] | • double-blind • parallel • randomized • placebo-controlled | 174 (84 on drug and 90 on placebo) | 100 mg tablets were up-titrated to a maximum dosage of 300 mg at bedtime; median dose: 236 mg | the frequency of RLS attacks/week decreased | 34/84 subjects on carbamazepine including 6 withdrawals; 20/88 subjects on placebo including 2 withdrawals | |
| Oxcarbazepine | Oztürk et al [46] | • case report | 1 | 150 mg bid twice a day | improvement per IRLS scale score | side effects were not reported in this case report |
| Jimenez-Trevino et al [47] | • case series | 3 | 300 mg up-titration to 600 mg at bedtime | excellent remission | 1 patient experienced mild dizziness but during the first week of treatment only | |
| Prescriber guidelines: boxed warning for carbamazepine and oxcarbazepine for the development of Stevens-Johnson syndrome and for the development of aplastic anemia and agranulocytosis; hyponatremia [48, 49] | ||||||
| Lamotrigine | Youssef et al [50] | • open-label • uncontrolled | 4 (3 completed the study) | 250 mg –500 mg/day; mean dose: 360 mg/day | 2/3 patients reported a sustained decrease in sensations, leg kicking and restlessness; 3/3 patients continued | 2/3 pruritis, 1/3 dizziness and 1/3 chest pain; 1 withdrawal due to dizziness |
| McMeekin et al [51] | • case series | 7 | slowly up-titrated | successful treatment | ||
| Prescriber guidelines: caution in patients with heart disease; boxed warning regarding the development of Stevens -Johnson Syndrome and other severe skin reactions [52] | ||||||
| Topiramate | Pérez Bravo et al [20]* | • open label • uncontrolled | 19 | a mean effective dosage of 42.1 mg | improvement 19 patients | weight loss; hepatic or renal impairment |
| Romigi et al [53] | • case series | 2 | slowly titrated up to 50 mg bid; up to 100 mg bid | provoking RLS | provoking RLS | |
| Bermejo et al [54] | • case series | 2 | titrated up to 50 mg bid; titrated up to 75 mg/day | provoking RLS | provoking RLS | |
| Prescriber guidelines: a warning for use in patients with hepatic or renal impairment; possibility of attention, memory and language problems [55] | ||||||
| Valproic Acid | Ehrenberg et al [56] | • open-label (for PLMS and not RLS) • uncontrolled | 6 | 125–600 mg at bedtime | subjective improvement in daytime alertness and sleep (REM sleep unchanged) | 1/6 short-term side effects; 1/6 weight gain |
| Eisensehr et al [57] | • double-blind • crossover (three comparator groups- Valproic Acid, L-DOPA and placebo) • randomized • placebo-controlled | 20 | 600 mg slow-release valproic acid or 200 mg slow-release levodopa + 50 mg benserazide 90 minutes before bedtime | decrease of intensity and duration of RLS symptoms was more pronounced with valproic acid than levodopa | 9/20; levodopa increased arousals not associated with PLMS; pressure in the chest, flatulence, difficulty falling asleep, drowsiness, edema, finger pain, headache, blurred vision, hand tremor and hair loss | |
| Prescriber guidelines: boxed warning for the possibility of hepatotoxicity, pancreatitis, and congenital malformations [58] | ||||||
| Levetiracetam | Della Marca et al [59] | • case series | 2 | 1000 mg at bedtime and 500 mg at bedtime | 2 patients improved per IRLS scale score, SIT, ESS, and in the sleep latency, sleep efficiency and PLMS index; both continued on the medication | |
| Gagliano et al [60] | • open-label • uncontrolled | 7 | titrated up to 50–60 mg/kg/day in two separate doses (in children) | improvement per IRLS scale score, sleep quality and fewer awakenings and restorative sleep; EEG focal interictal epileptic discharges in sleep | mild: 2/7 increase in appetite and in daytime irritability | |
| Prescriber guidelines: possibility of the development of rare but severe cutaneous reactions such as the Stevens-Johnson syndrome; renal failure; psychiatric side effects, including psychosis, paranoid ideation, and behavioral instability, may also occur [61] | ||||||
| 3.5. Steroids And The Auto-Immune, Anti-Inflammatory Link | ||||||
| Hydrocortisone | Hornyak et al [63] | • double-blind • crossover • randomized • placebo-controlled | 10 (5 on drug and 5 on placebo) | 40 mg prior to a one hour SIT | decrease in sensory leg discomfort; 5/10 subjective improvement | none |
| Oral Prednisolone | Oscroft et al [64] | • case report | 1 | 15 mg/day; tapered to a minimum effective dose of 8 mg/day | Improvement per IRLS scale score; ESS | |
| Prescriber guidelines: potential long term consequences such as osteoporotic fractures, hypertension, steroid-induced diabetes and changes in physical appearance such as moon face and buffalo hump [64, 65, 66] | ||||||
| 3.6. Other Medications And Substances | ||||||
| Cannabinoids | Megelin et al [67] | • case series | 6 | occasional and recreational smoking; sublingual administration of cannabidiol | 6 patients well tolerated | 1/6 nausea therefore restricted smoking to periods with symptom severity exacerbation |
| Samaha et al [68] | • survey | 192 (15 responded to use cannabis | cannabis use | 9/15 reported improvement | ||
| Prescriber guidelines: monitoring for potential CNS depression, hepatic impairment, and suicidal ideation [69] | ||||||
| Bupropion | Park et al [71] | • case report | 1 | 150 mg daily up to 300 mg | improvement per IRLS scale score; total resolution | |
| Lee et al [72] | • case report | 1 | 150 mg daily | “feeling good”; able to initiate and maintain sleep for 7–8 hours nightly | ||
| Kim et al [73] | • case series | 3 | 150 mg sustained-release (SR) bupropion morning once per day | 2/3 Improvement per IRLS scale score, sleep (un)changed minimally | ||
| Bayard et al [74] | • double-blind • parallel • randomized • placebo-controlled | 60 (29 on drug and 31 on placebo); with drop-outs at 3 and 6 weeks | 150 mg XL/day two hours before bedtime | improvement per IRLS scale score only at 3 weeks | withdrawals: 1/29 - nausea; 1/29 – miscarriage; 2/29 – no reason; 2/31 – nausea; 1/31 irritable mood; 1/31 – no reason | |
| Vishwakarma et al [75] | • double-blind • parallel (three active comparators Bupropion, ropinirole and iron) • randomized | 103 (30 in each group); 13 drop-outs | 300 mg/day, ropinirole 0.5 mg/day or oral iron 150 mg elemental formulation along with vitamin C | all groups improvement per IRLS scale score (particularly the ropinirole group), RLS Quality of Life | 9/99 patients; nausea, dizziness, tremor, tingling sensation in palm and sole, gastritis, constipation, and weight gain | |
| Prescriber guidelines: a boxed warning alerting prescribers to the possibility of suicidal thoughts and behavior [76] | ||||||
| Baclofen | Guilleminault et al [77] | • double-blind (for PLMS only – not RLS) • placebo at baseline was used as comparator to medication given thereafter • crossover • placebo-controlled | 5 | 20 mg up-titration to 160 mg at 9:45 PM; dosages of 20 mg and 40 mg were the most efficacious | Improvement in 5 patients; effect on sleep was dose related: as dosages increased, delta sleep progressively increased and REM sleep decreased | 2/5 nausea, during the night at the 80 mg dosage, which may explain the overall decrease in total sleep time (TST) at this dosage, and the moderate increase in wake after sleep onset |
| Sandyk et al [78] | • case report | 1 | 10 mg nightly | Patient improved sleep, daytime somnolence, RLS | ||
| Brown et al [79] | • case report | 1 | 1204 mcg/day intrathecal baclofen | no improvement | ||
| Prescriber guidelines: very slowly withdrawing patients on intrathecal baclofen due to the possibility of developing high fever, confusion and, in some cases, rhabdomyolysis, multiple organ failure and death [80] | ||||||
| Physostigmine | Alpert et al [81] | • case report | 1 | 1 mg IV | Sixty to 90 s after the administration all leg movement ceased | |
| Peacock et al [82] | • case report | 1 | 1 mg IV | 3 minutes after the administration all symptoms attenuated | ||
| Prescriber guidelines: contraindications of using physostigmine in patients with gastrointestinal or genitourinary obstruction, asthma, cardiovascular disease, and may cause arrythmias, or seizures [83] | ||||||
| Orphenadrine Citrate | Popkin et al [18]* | • open-label • uncontrolled | 32; (20 on drug) 12 drop-outs | oral dosage of 100 mg (occasionally 200 mg) daily for 1 or 2 divided doses in the evening | 16/20 long-term excellent results (subjectively) | 12/32 discontinued due to gastrointestinal intolerance |
| Prescriber guidelines: not to be used in older adults because of an increased risk of anticholinergic effects, sedation and risk of fracture; caution in patients with heart disease and drug or alcohol abuse [84] | ||||||
| Rifaximin | Weinstock et al [86] | • open-label • uncontrolled | 13 | 400mg three times daily; 1200 mg/day for 10 days | 6/13 patients complete resolution; 86% overall long term improvement | |
| Weinstock et al [87] | • open-label • uncontrolled | 14 | 1200 mg/day for 10 days followed by 400 mg every other day | global improvement in 9/14 patients per IRLS score | ||
| Prescriber guidelines: warnings to observe for allergic reactions and super-infections with other organisms [88] | ||||||
| Botulinum toxin (BTX) | Rotenberg et al [89] | • case series | 3 | BTX-A (100 units per cc) was injected into each of his tibialis anterior muscles bilaterally, in divided doses of 25 units, with a total of 50 units per muscle; a total of 320 units of BTXA (100 units per cc) bilaterally in his lumbar paraspinal muscles (40 units per site, in 2 sites per side), his gastrocnemii (20 units per site and 2 sites per leg), and his quadratus femorii (20 units per site and 2 sites per leg); a total of 70 units of BTX-A (50 units per cc) were administered subcutaneously in the dysesthetic areas (5 units per site and 7 sites per leg) | Improvement subjective and ESS | 1/3 patients experienced residual weakness |
| Mittal et al [90] | • double-blind • crossover • randomized • placebo-controlled | 24 (8 on drug and 13 on placebo); 3 drop-outs | 100 units of Incobotulinumtoxin A (IncoA) | 21 patients improved per IRLS, ESS and the sleep questionnaire score; 7/21 definite or marked improvement on CGI | none with residual weakness | |
| Agarwal et al [91] | • open-label • uncontrolled | 8 | received 50 units of onabotulinum toxin A, two points of injection were used per tibialis anterior | 8 cases; improvement per PGI-S | none with residual weakness | |
| Ghorayeb et al [92] | • open-label • uncontrolled | 27 (26 completed the study) | 20 intradermal injections of 0.05 ml of BoNT/A | 6/27 improved per IRLS scale score; 10/27 improvement per CGI-I scores | 7/27 patients experienced transient limb weakness; 1/27 reported to have diplopia; 1 withdrawal due to lack of efficacy after week 12 | |
| Nahab et al [93] | • double-blind • crossover • placebo-controlled | 6 | IM injections of 70–320 mouse units (mU) of botulinum toxin type A | 6/6 patients without improvement per IRLS scale or CGI | 2/6 patients experienced weakness | |
| Prescriber guidelines: black box warning of dysphagia and breathing difficulties, bacteriuria, urinary retention and tract infection, and anaphylaxis hypersensitivity reaction [95] | ||||||
| Selegiline | Grewal et al [96] | • open-label(for PLMS only – not RLS) • retrospective • uncontrolled | 31 | 5mg bid for 2 weeks (n = 5 at end of follow-up period); increased to 10mg bid for next 2 weeks (n = 5 at end of follow-up period); then lastly increased to 15mg bid for last two weeks (n = 21 at end of follow-up) | PLMS were suppressed in the total group by 21.2/hr (pretreatment 35.6/hr and post-treatment 14.5/hr) (p < 0.0005) as determined by polysomnography The subgroup of 21 patients who were on 15mg bid treatment dosage saw PLMS reduction by 20.7/hr (p < 0.0005) | 4/31 patients experienced slight feelings of disconnection, nervousness, and nausea |
| Prescriber guidelines: using selegiline include orthostatic hypotension, vertigo, palpitation, suicidal thinking/behavior, dyskinesia, psychosis, and CNS depression [97] | ||||||
[i] *: Information based on abstract; CGI: Clinical Global Impression; ESS: Epworth Sleepiness scale; IRLS scale: International Restless Legs Syndrome Study Group’s Symptom Rating Scale; IV: intravenous; mSIT: Multiple Suggested Immobilization Tests; PGI-S: Patient Global Impression-Severity; PLMS: Periodic Limb Movements in Sleep; RCT: Randomized Controlled Trial; SIT: Suggested Immobilization Test. Side/Adverse Effects from the studies themselves are listed vertically in the column Side/Adverse Effects. Side effects from the broader literature are listed horizontally under each group of medications.
Table 2
Studies employing the International Restless Legs Scale (IRLS) (mean ± standard deviation): Baseline and endpoint scores are provided.
| DRUG | AUTHOR | METHOD | IRLS SCALE SCORE | CGI SCORE | MSIT |
|---|---|---|---|---|---|
| Dipyridamole | Garcia-Borreguero et al [33 | baseline | 23.4 ± 4.6 | 3.5 ± 0.5 | 26.6 ± 9.8 (3 tests) |
| endpoint | 10.7 ± 4.5 | 1.7 ± 0.7 | 18.9 ± 7.5 (3 tests) | ||
| Dipyridamole | Garcia-Borreguero et al[34 | baseline | 24.1 ± 3.1 | 3.2 ± 0.9 | 15.6 ± 8.6 (subjective scale) |
| endpoint | 11.1 ± 2.3 | 1.3 ± 0.6 | 28.3 ± 7.2 (subjective scale) | ||
| Perampanel | Garcia-Borreguero et al[38 | baseline | 23.7 ± 4.2 | 3.6 ± 0.48 | 44.2±14.5 (4 tests) |
| endpoint | 11.5 ± 5.2 | 1.8 ± 0.74 | 27.3±10.7 (4 tests) | ||
| Oxcarbazepine | Oztürk et al[46 | case 1 baseline | 32 | ||
| case 1 endpoint | 19 | ||||
| Levetiracetam | Della Marca et al[59 | case 1 & 2 baseline | 34 & 27 | 39 & 45 SIT PLMS index (events/h) | |
| case 1 & 2 endpoint | 22 & 18 | 11 & 21 SIT PLMS index (events/h) | |||
| Levetiracetam | Gagliano et al[59 | baseline | 18.9 ± 2.6 | ||
| endpoint | 4.7 ± 4.9 | ||||
| oral prednisolone | Oscroft et al[64 | case 1 baseline | 22 | ||
| case 1 endpoint | 14 | ||||
| Bupropion | Park et al[71 | case 1 baseline | 26 | ||
| case 1 endpoint | 14 | ||||
| Bupropion | Kim et al[73 | case 1 & 2 & 3 baseline | 24 & 22 & 23 | ||
| case 1 & 2 & 3 endpoint | 9 & 10 & 0 | ||||
| Bupropion | Bayard et al[74 | baseline | 26.3 ± 5.4 | ||
| endpoint | 15.9 ± 9.1 | ||||
| Botulinum toxin (BTX) | Mittal et al[90 | endpoint | 27 ± 7.13 | ||
| Botulinum toxin (BTX) | Ghorayeb et al[92 | baseline | 31.1 ± 4.7 | ||
| endpoint | 22.3 ± 8.5 | ||||
| follow-up | 26.1 ± 7.2 | ||||
| Botulinum toxin (BTX) | Nahab et al[93 | baseline | 27 ± 4.8 | 4.3 ± 0.8 | |
| improvement | 5 ± 6 | 3.7 ± 1.4 |
[i] CGI: Clinical Global Impression; IRLS scale: International Restless Legs Syndrome Study Group’s Symptom Rating Scale; mSIT: Multiple Suggested Immobilization Tests For all studies that employed the IRLS data could be extracted, except for Vishwakarma et al [75], Mittal et al [90 and Evidente et al [40].
Figure 1
Scheme of reviewed drugs.
Supplementary Figure S1 Flowchart of the selected studies.