Figure 1
Research Prisma.
Table 1
Non- pharmacological Treatments of CKD-A-RLS.
| MODE OF TREATMENT | NUMBER OF PATIENTS | TYPE OF STUDY | DURATION OF TREATMENT | RESULTS | SIDE EFFECTS |
|---|---|---|---|---|---|
| Aerobic exercise [37] | Treatment 7 Control 7 | Prospective, Open label | 16 weeks | Reduced IRLS score by 42% Improved QoL: P = 0.03 Functional ability: P = 0.02 Sleep quality P = 0.01 | None |
| Aerobic exercise [38] | Treatment 13 Control 13 All on hemodialysis | Prospective, Open label | 16 weeks Bicycling 3 times/week | IRLS scores improved on week 16; no improvement of quality of life | None |
| Glycerin and lavender oil massage [39] | Glycerin 35 Lavender 35 Control 35 All on hemodialysis | Prospective Open label | 45 minute, 3 times a week for one month | At the end of the study, both glycerin and lavender oil significantly improved symptoms (P < 0.05) | None |
| Lavender oil and sweet orange oil massage [40] | Lavender 35 Sweet orange 35 Control 35 All on hemodialysis | Double blind, Controlled | 3 weeks, 3 times a week | At the end of the study, both glycerin and sweet orange significantly improved symptoms (P < 0.001) | None |
| Lavender oil massage [41] | Lavender 21 Control 21 | Double blind Controlled | 4 weeks | At the end of the study, lavender oil significantly improved symptoms (P < 0.0001) | None |
| Lavender oil massage [42] | Lavender 31 Control 26 (baby oil) | Placebo Controlled | 10 minutes massage, 3 times per week for 4 weeks | RLS severity decreased and QoL improved significantly in the lavender group (P < 0.001) | None |
| Lavender oil massage [43] | Lavender 29 Control 30 | Placebo Controlled | 10 minutes, 3 times per week | RLS severity significantly decreased in the lavender group (P < 0.0001) | None |
| Application of infrared light at acuopoints [44] | Treatment 30 Control 30 | Single blind Prospective | 3 times per week for 3 weeks | Reduced IRLSRS scores but only during treatment | None |
Table 2
Pharmacological Treatment of CKD-A-RLS.
| NAME OF THE DRUG (S) | DESIGN OF STUDY | NUMBER OF PATIENTS, DOSE | RESULTS | SIDE EFFECTS |
|---|---|---|---|---|
| Levodopa [45] | Double blind, cross over for 4 weeks | 15, 100 & 200 mg | Improved leg movements, PLM index, sleep quality and QoL (Ps < 0.03) | Dry mouth and headaches |
| Gabapentin [46] | Double blind, crossover for 4 weeks (1 week wash out) | 15, 200 & 300 mg | 11 patients responded to gabapentin,1 to both placebo and gabapentin | Two drop-outs, one due to lethargy, one due to MI (unrelated to drug) |
| Rotigotine patch, Stage 2 CKD [47] | Single center Prospective, open label | 14, 1 mg, 2 mg | Improved: severity of Symptoms (p < 0.003), QoL (P < 0.001, sleep (P < 0.001). | One patient:GI upset, no augmentation |
| Gabapentin [48] | Single center, Retrospective | 59: GP 50 and 100 mg 125: controls | No effect | In gabapentin group, 17% discontinued treatment |
| Rotigotine patch [49] CKD/HD | Double blind, placebo controlled | 15 Rotigotine 1 to 3 mg, 3 times daily for 3 weeks 10 Placebo | At the end of study: 10 of 15 and 2 of 10 showed significant improvement of RLS score in Rotigotine and placebo groups, respectively. | Nausea 20% Vomiting 15% |
| Low dose ropinirole vs aerobic exercise vs placebo 4 hours HD, 3 sessions/week [50] | Partially, double blind/placebo controlled | 0.25 mg ropinirole, 2 h before sleep, 45 minutes cycling during each HD session Ropinirole 7 Exercise 15 Placebo 7 | Ropinirole and aerobic exercise equally improved IRLS scores, QoL and depression. Ropinirole improved sleep quality | No side effects |
| Gabapentin (GP) versus Levodopa (LD) [51] | Double blind | GP: 42 LD: 40 GP: 200 mg/d LD: 110 mg/d Over 4 weeks | Both reduced IRLS scores but GP was more effective (P < 0.016). Both improved quality of sleep | Transient hypotension in two patients who took Levodopa. Increased day time sleepiness GP > LD |
| Gabapentin (GP) versus Levodopa (LD) [52] Hemodialysis: 3 times/week | Observational Cross sectional | GP: 14 LD: 12 GP: 200 mg/after each dialysis session LD: 110 mg/day 4 weeks treatment duration | IRLSS score was significantly improved after both Gabapentin and Levodopa treatment (P = 0.0001). Gabapentin was superior to L-Dopa in improving quality of sleep and QoL | Not mentioned |
| Gabapentin versus levodopa [53] Hemodialysis 3 times/week | Open label Prospective | GP# 15 LD#15 Gabapentin: 200 mg after each dialysis session LD: 125 mg, 2 hours before sleep | Both improved IRLSS scores. Gabapentin was superior to levodopa in improving sleep quality and latency, QoL (measured by SF36), general health and body pain | One patient dropped from the study due to gabapentin side effect (type not mentioned). |
| Ropinirole versus levodopa-SR [54] Chronic hemodialysis patients | Randomized, cross-over | 10 Levodopa 190 mg/day Ropinirole 1.45 mg/day Duration 14 weeks (4 weeks each trial with 6 weeks washout) | At the end of study, ropinirole was superior to levodopa regarding improving scores of six item IRLS and increasing sleep time (P < 0.001) as well as improvement of clinical impression scorea (P < 0.01) | One patient taking levodopa withdrew from the study due to vomiting |
[i] GP: gabapentin; LD: levodopa; QOL-quality of life; HD: hemodialysis.
Table 3
Vitamin C and E treatment for CKD-A-RLS.
| TYPE OF VITAMIN | NUMBER OF PATIENTS | STUDY DESIGN | DOSE AND DURATION OF TREATMENT | RESULTS | SIDE EFFECTS |
|---|---|---|---|---|---|
| C and E [55] | 60 Divided in 4 groups each including 15 patients Group 1: C + P Group 2: E + P Group 3: C + E Group 4: double placebo | Double blind-placebo controlled | Vitamin C: 200 mg/day Vitamin E: 400 mg/day All treatments for 8 weeks | At 8 weeks, patients treated with vitamin C or E or both demonstrated significant reduction of IRLS score compared to placebo. The difference between vitamin treated groups was not significant. | none |
| Intravenous Vitamin C [56] | 90 | Double blind placebo controlled | Intravenous Vitamin C, three times per week (given at the end of dialysis session for 8 weeks. | Quality of sleep and RLS scores improved significantly in patients who received vitamin C. | None |
| Compared Vitamin C with pramipexole [57] | 45 Divided in three group each including 15 patients Group 1: Vitamin C Group 2: pramipexole Group 3-: placebo | Double blind placebo controlled | Vitamin C: 250 mg Pramipexole: 0.18 mg Vitamin C, pramipexole and placebo were given once daily for 8 weeks | Both Vitamin C and Pramipexole groups demonstrated significant improvement of IRLS scores after treatment (P < 0.001). | One patient in the pramipexole developed nausea and vomiting and excluded |
Table 4
Intravenous Iron Therapy for RLS-A-CKS.
| TREATMENT | NUMBER OF PATIENTS | STUDY DESIGN | DOSE, DURATION | RESULTS | SIDE EFFECTS |
|---|---|---|---|---|---|
| Intravenous (IV) iron dextran [58] | 25 Iron dextran: 11 Placebo: 14 | Double blind- placebo controlled | Iron dextran: 1000 mg Study duration: 4 weeks. IRLS intensity scores were assessed weekly | At weeks 1 and 2 post-injection, patients in the Iron treated group showed significant reduction of IRLS scores (P = 0.01 and P = 0.03). At week 4, though still lower than placebo, the difference was not statistically significant | No difference in adverse effects between the two groups |
| Intravenous iron sucrose [59] | 30 IV Iron Sucrose: 16 Placebo: 16 | Randomized, placebo-controlled | Iron sucrose: 100 mg, three times/week for a total of 1000 mg. Study duration: 3 weeks | After two weeks, IRLS scores (compared to baseline) were significantly reduced compared to placebo group (P = 0.000). Improvement of IRLS score in the iron group continued for 4–24 weeks. | No adverse effects |
| Intravenous iron sucrose [60] | 18 Iron sucrose:11 Placebo:7 | Double blind- placebo controlled | 500 mg of Iron sucrose was administered IV in two successive days for a total of 1000 mg Study duration: 4 weeks Primary outcome for RLS symptom improvement was global rating scale (GRS) | The trial was aborted half- way into the study since despite some improvement in GRS (at two weeks), authors predicted lack of robust response at the end of the study | Edema in either hands or feet (36%). Nausea or vomiting (36%). Hypotension (18%). dizziness (18%). abdominal pain (9%). All noted during infusion only. |
[i] GRS: Global rating Scale.
Table 5
Double-blind, placebo-controlled studies of narcotic treatment in restless legs syndrome-.
| AUTHORS AND DATE | NUMBER OF PATIENTS | DRUG, DOSE, STUDY DURATION | RESULTS | SIDE EFFECTS |
|---|---|---|---|---|
| *Walters et al, 1993 [61] | 11 | Oxycodone, 5 mg tablets, average dose 15.9 mg/day Study duration: two weeks | Patients rated improvement on the scale of 1–4: leg sensations, daytime sleepiness, motor restlessness and PLS. All Significantly improved (P < 0.5), | Mild constipation: two patients, mild lethargy: 1 patient |
| **Trenkwalder et al, 2009 [62] | 267 | Oxycodone/Naloxone (longacting), starting dose 5 mg/2.5 mg twice daily increasing up to 40/20 mg per research’s discretion. Study duration: 12 weeks | Mean International RLS Study group severity rating scale Sum score significantly improved in oxycodone group At week 12 (P < 0.0001) | Serious adverse effects: 3 in the double blind phase, 3 in the extension phase.(not specified). |
[i] * Double-blind, crossover; ** Double-blind, parallel design; PLS: periodic leg movements of sleep.
Table 6
Diagnostic criteria defined for diagnosis of RLS by International Restless Legs Society, (last revision 2014).
| 1 | An irresistible urge to move the legs, usually but not always accompanied by uncomfortable and unpleasant sensations in the legs |
| 2 | Symptoms that begin or worsen during the periods of inactivity, such as lying down or sitting |
| 3 | Symptoms are partially or totally relieved by movement |
| 4 | Symptoms only occur and are worse in the evening or night than during the day |
| 5 | The occurrence of the described features is not solely accounted for as symptoms primary to another medical or a behavioral condition (myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping). The criteria published earlier in 2003 lacks the 5th criteria. |
Table 7
Dose adjustment recommended for gabapentin and pregabalin in kidney failure [66].
| DRUG’S NAME | BASED ON CREATINE CLEARANCE (ML/MINUTE) | RECOMMENDED DOSE GIVEN IN THREE DIVIDED DOSES IN ALTERNATE DAYS |
|---|---|---|
| Gabapentin | 50–79 | 600–180 mg |
| 30–49 | 300–900 mg | |
| 15–29 | 150–600 | |
| <15 | 150–300 | |
| Pregabalin | Based on eGFR, mL/min/1.73 m2 | |
| 30–60 | Initially 75 mg, maximum 300 mg daily | |
| 15–30 | Initially 25–50 mg, maximum 300 mg in two divided doses | |
| <30 | Initially 25 mg once daily and maximum 75 mg once daily |