Efficacy and safety of medicines for restless legs syndrome: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Qian , CHEN Xiangting ,  ZHOU Changqing

Department of Neurology, Bishan Hospital of Chongqing Medical University, Chongqing 402760, P. R. China;

Corresponding?author：

ZHOU Changqing, Email: changqing_zhou@163.com

Keywords：

Restless legs syndrome; Dopamine agonists; Network meta-analysis

DOI：

10.7507/1672-2531.202202051

Video：

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Objective To systematically review the efficacy and safety of non-ergoline dopamine agonists (pramipexole, ropinirole, and rotigotine) and α2δ ligands (pregabalin and gabapentin-enacarbil) in the treatment of restless legs syndrome (RLS). Methods The PubMed, EMbase, The Cochrane Library, CBM, WanFang Data, and CNKI databases were electronically searched for randomized controlled trials (RCTs) assessing different medications for RLS from 2000 to 2021. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. The network meta-analysis was then performed using Stata 16.0 software and R 4.1.0 software. Results A total of 36 RCTs involving 7 666 patients were included. The results of the network meta-analysis showed that gabapentin-enacarbil decreased IRLS scores to the greatest extent among all drugs (MD=?6.42, 95%CI ?8.8 to ?4.16), was superior to pramipexole (MD=?3.27, 95%CI ?6.54 to ?0.15), and was associated with the highest CGI-I response rates (RR=1.73, 95%CI 1.52 to 2.00). In terms of tolerance and safety, patients receiving rotigotine presented an increased incidence of withdrawal due to adverse events. Ropinirole had the highest incidence of nausea. Headache was most common side effect in rotigotine, while the incidences of somnolence and dizziness were higher in gabapentin-enacarbil than other treatments. Conclusion Current evidence suggests that gabapentin-enacarbil may be the best treatment for RLS. Rotigotine is associated with the worst tolerance. For safety, nausea is most common in ropinirole, headache is most common for rotigotine, and patients receiving gabapentin-enacarbil show increased incidences of somnolence and dizziness.

Citation： ZHANG Qian, CHEN Xiangting, ZHOU Changqing. Efficacy and safety of medicines for restless legs syndrome: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2022, 22(8): 908-916. doi: 10.7507/1672-2531.202202051 Copy

1.	中國醫師協會神經內科醫師分會睡眠學組, 中華醫學會神經病學分會睡眠障礙學組, 中國睡眠研究會睡眠障礙專業委員會. 中國不寧腿綜合征的診斷與治療指南(2021版). 中華醫學雜志, 2021, 101(13): 908-925.
2.	Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord, 2011, 26(1): 114-120.
3.	Winkelman JW, Redline S, Baldwin CM, et al. Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. Sleep, 2009, 32(6): 772-778.
4.	Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med, 2006, 7(7): 545-552.
5.	Fr?hlich AC, Eckeli AL, Bacelar A, et al. Brazilian consensus on guidelines for diagnosis and treatment for restless legs syndrome. Arq Neuropsiquiatr, 2015, 73(3): 260-280.
6.	Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology. Neurology, 2016, 87(24): 2585-2593.
7.	Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med, 2016, 21: 1-11.
8.	Iftikhar IH, Alghothani L, Trotti LM. Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis. Eur J Neurol, 2017, 24(12): 1446-1456.
9.	Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology, 2006, 67(6): 1034-1039.
10.	Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord, 2007, 22(2): 213-219.
11.	Ferini-Strambi L, Aarskog D, Partinen M, et al. Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial. Sleep Med, 2008, 9(8): 874-881.
12.	H?gl B, Garcia-Borreguero D, Trenkwalder C, et al. Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome. Sleep Med, 2011, 12(4): 351-360.
13.	Montagna P, Hornyak M, Ulfberg J, et al. Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood. Sleep Med, 2011, 12(1): 34-40.
14.	Ma JF, Wan Q, Hu XY, et al. Efficacy and safety of pramipexole in chinese patients with restless legs syndrome: results from a multi-center, randomized, double-blind, placebo-controlled trial. Sleep Med, 2012, 13(1): 58-63.
15.	Garcia-Borreguero D, Patrick J, DuBrava S, et al. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. Sleep, 2014, 37(4): 635-643.
16.	Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med, 2014, 370(7): 621-631.
17.	Zhang J, Liu B, Zheng Y, et al. Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study. Sleep Med, 2015, 16(1): 181-185.
18.	Adler CH, Hauser RA, Sethi K, et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial. Neurology, 2004, 62(8): 1405-1407.
19.	Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry, 2004, 75(1): 92-97.
20.	Walters AS, Ondo WG, Dreykluft T, et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord, 2004, 19(12): 1414-1423.
21.	Bogan RK, Fry JM, Schmidt MH, et al. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc, 2006, 81(1): 17-27.
22.	Montplaisir J, Karrasch J, Haan J, et al. Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial. Mov Disord, 2006, 21(10): 1627-1635.
23.	Kushida CA, Geyer J, Tolson JM, et al. Patient- and physician-rated measures demonstrate the effectiveness of ropinirole in the treatment of restless legs syndrome. Clin Neuropharmacol, 2008, 31(5): 281-286.
24.	Benes H, Mattern W, Peglau I, et al. Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS patients: a multicentre, randomized, placebo-controlled study. J Neurol, 2011, 258(6): 1046-1054.
25.	Giannaki CD, Sakkas GK, Karatzaferi C, et al. 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. BMC Nephrol, 2013, 14: 194.
26.	Giorgi L, Asgharian A, Hunter B. Ropinirole in patients with restless legs syndrome and baseline IRLS total scores ≥ 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clin Ther, 2013, 35(9): 1321-1336.
27.	Stiasny-Kolster K, Kohnen R, Schollmayer E, et al. 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. Mov Disord, 2004, 19(12): 1432-1438.
28.	Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol, 2008, 7(7): 595-604.
29.	Oertel WH, Benes H, Garcia-Borreguero D, et al. Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe. Sleep Med, 2008, 9(3): 228-239.
30.	Hening WA, Allen RP, Ondo WG, et al. Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States. Mov Disord, 2010, 25(11): 1675-1683.
31.	Oertel WH, Benes H, Garcia-Borreguero D, et al. Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: a randomized, placebo-controlled polysomnographic study. Sleep Med, 2010, 11(9): 848-856.
32.	Inoue Y, Shimizu T, Hirata K, et al. Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study. Sleep Med, 2013, 14(11): 1085-1091.
33.	Garcia-Borreguero D, Allen R, Hudson J, et al. Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study. Curr Med Res Opin, 2016, 32(1): 77-85.
34.	Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med, 2010, 11(6): 512-519.
35.	Kushida CA, Becker PM, Ellenbogen AL, et al. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology, 2009, 72(5): 439-446.
36.	Kushida CA, Walters AS, Becker P, et al. A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. Sleep, 2009, 32(2): 159-168.
37.	Walters AS, Ondo WG, Kushida CA, et al. Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol, 2009, 32(6): 311-320.
38.	Bogan RK, Bornemann MA, Kushida CA, et al. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc, 2010, 85(6): 512-521.
39.	Lee DO, Ziman RB, Perkins AT, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. J Clin Sleep Med, 2011, 7(3): 282-292.
40.	Winkelman JW, Bogan RK, Schmidt MH, et al. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord, 2011, 26(11): 2065-2072.
41.	Lal R, Ellenbogen A, Chen D, et al. 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. Clin Neuropharmacol, 2012, 35(4): 165-173.
42.	Inoue Y, Hirata K, Uchimura N, et al. Gabapentin enacarbil in Japanese patients with restless legs syndrome: a 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Curr Med Res Opin, 2013, 29(1): 13-21.
43.	Winkelman JW, Jaros MJ. Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome. Sleep Med, 2018, 48: 1-7.
44.	Garcia-Borreguero D, Cano-Pumarega I, Garcia Malo C, et al. Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment. Sleep Med, 2019, 55: 74-80.
45.	Cope S, Jansen JP. Quantitative summaries of treatment effect estimates obtained with network meta-analysis of survival curves to inform decision-making. BMC Med Res Methodol, 2013, 13: 147.
46.	Zhou X, Du J, Liang Y, et al. The efficacy and safety of pharmacological treatments for restless legs syndrome: systemic review and network meta-analysis. Front Neurosci, 2021, 15: 751643.
47.	Ahmed M, Hays R, Steven PJ, et al. Effect of gabapentin enacarbil on individual items of the international restless legs study group rating scale and post-sleep questionnaire in adults with moderate-to-severe primary restless legs syndrome: pooled analysis of 3 randomized trials. Clin Ther, 2016, 38(7): 1726-1737.
48.	Avidan AY, Lee D, Park M, et al. The effect of gabapentin enacarbil on quality of life and mood outcomes in a pooled population of adult patients with moderate-to-severe primary restless legs syndrome. CNS Drugs, 2016, 30(4): 305-316.
49.	Allen R, Oertel W, Walters A, et al. Relation of the international restless legs syndrome study group rating scale with the clinical global impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. Sleep Med, 2013, 14(12): 1375-1380.
50.	Ferré S, García-Borreguero D, Allen RP, et al. New insights into the neurobiology of restless legs syndrome. Neuroscientist, 2019, 25(2): 113-125.
51.	Yepes G, Guitart X, Rea W, et al. Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Ann Neurol, 2017, 82(6): 951-960.
52.	Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med, 2014, 15(11): 1288-1301.
53.	Vellieux G, d'Ortho MP. Restless legs syndrome. Rev Med Interne, 2020, 41(4): 258-264.

1. 中國醫師協會神經內科醫師分會睡眠學組, 中華醫學會神經病學分會睡眠障礙學組, 中國睡眠研究會睡眠障礙專業委員會. 中國不寧腿綜合征的診斷與治療指南(2021版). 中華醫學雜志, 2021, 101(13): 908-925.
2. Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord, 2011, 26(1): 114-120.
3. Winkelman JW, Redline S, Baldwin CM, et al. Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. Sleep, 2009, 32(6): 772-778.
4. Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med, 2006, 7(7): 545-552.
5. Fr?hlich AC, Eckeli AL, Bacelar A, et al. Brazilian consensus on guidelines for diagnosis and treatment for restless legs syndrome. Arq Neuropsiquiatr, 2015, 73(3): 260-280.
6. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology. Neurology, 2016, 87(24): 2585-2593.
7. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med, 2016, 21: 1-11.
8. Iftikhar IH, Alghothani L, Trotti LM. Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis. Eur J Neurol, 2017, 24(12): 1446-1456.
9. Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology, 2006, 67(6): 1034-1039.
10. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord, 2007, 22(2): 213-219.
11. Ferini-Strambi L, Aarskog D, Partinen M, et al. Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial. Sleep Med, 2008, 9(8): 874-881.
12. H?gl B, Garcia-Borreguero D, Trenkwalder C, et al. Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome. Sleep Med, 2011, 12(4): 351-360.
13. Montagna P, Hornyak M, Ulfberg J, et al. Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood. Sleep Med, 2011, 12(1): 34-40.
14. Ma JF, Wan Q, Hu XY, et al. Efficacy and safety of pramipexole in chinese patients with restless legs syndrome: results from a multi-center, randomized, double-blind, placebo-controlled trial. Sleep Med, 2012, 13(1): 58-63.
15. Garcia-Borreguero D, Patrick J, DuBrava S, et al. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. Sleep, 2014, 37(4): 635-643.
16. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med, 2014, 370(7): 621-631.
17. Zhang J, Liu B, Zheng Y, et al. Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study. Sleep Med, 2015, 16(1): 181-185.
18. Adler CH, Hauser RA, Sethi K, et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial. Neurology, 2004, 62(8): 1405-1407.
19. Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry, 2004, 75(1): 92-97.
20. Walters AS, Ondo WG, Dreykluft T, et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord, 2004, 19(12): 1414-1423.
21. Bogan RK, Fry JM, Schmidt MH, et al. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc, 2006, 81(1): 17-27.
22. Montplaisir J, Karrasch J, Haan J, et al. Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial. Mov Disord, 2006, 21(10): 1627-1635.
23. Kushida CA, Geyer J, Tolson JM, et al. Patient- and physician-rated measures demonstrate the effectiveness of ropinirole in the treatment of restless legs syndrome. Clin Neuropharmacol, 2008, 31(5): 281-286.
24. Benes H, Mattern W, Peglau I, et al. Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS patients: a multicentre, randomized, placebo-controlled study. J Neurol, 2011, 258(6): 1046-1054.
25. Giannaki CD, Sakkas GK, Karatzaferi C, et al. 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. BMC Nephrol, 2013, 14: 194.
26. Giorgi L, Asgharian A, Hunter B. Ropinirole in patients with restless legs syndrome and baseline IRLS total scores ≥ 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clin Ther, 2013, 35(9): 1321-1336.
27. Stiasny-Kolster K, Kohnen R, Schollmayer E, et al. 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. Mov Disord, 2004, 19(12): 1432-1438.
28. Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol, 2008, 7(7): 595-604.
29. Oertel WH, Benes H, Garcia-Borreguero D, et al. Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe. Sleep Med, 2008, 9(3): 228-239.
30. Hening WA, Allen RP, Ondo WG, et al. Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States. Mov Disord, 2010, 25(11): 1675-1683.
31. Oertel WH, Benes H, Garcia-Borreguero D, et al. Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: a randomized, placebo-controlled polysomnographic study. Sleep Med, 2010, 11(9): 848-856.
32. Inoue Y, Shimizu T, Hirata K, et al. Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study. Sleep Med, 2013, 14(11): 1085-1091.
33. Garcia-Borreguero D, Allen R, Hudson J, et al. Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study. Curr Med Res Opin, 2016, 32(1): 77-85.
34. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med, 2010, 11(6): 512-519.
35. Kushida CA, Becker PM, Ellenbogen AL, et al. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology, 2009, 72(5): 439-446.
36. Kushida CA, Walters AS, Becker P, et al. A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. Sleep, 2009, 32(2): 159-168.
37. Walters AS, Ondo WG, Kushida CA, et al. Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol, 2009, 32(6): 311-320.
38. Bogan RK, Bornemann MA, Kushida CA, et al. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc, 2010, 85(6): 512-521.
39. Lee DO, Ziman RB, Perkins AT, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. J Clin Sleep Med, 2011, 7(3): 282-292.
40. Winkelman JW, Bogan RK, Schmidt MH, et al. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord, 2011, 26(11): 2065-2072.
41. Lal R, Ellenbogen A, Chen D, et al. 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. Clin Neuropharmacol, 2012, 35(4): 165-173.
42. Inoue Y, Hirata K, Uchimura N, et al. Gabapentin enacarbil in Japanese patients with restless legs syndrome: a 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Curr Med Res Opin, 2013, 29(1): 13-21.
43. Winkelman JW, Jaros MJ. Predictors of clinical response in a double-blind placebo controlled crossover trial of gabapentin enacarbil for restless legs syndrome. Sleep Med, 2018, 48: 1-7.
44. Garcia-Borreguero D, Cano-Pumarega I, Garcia Malo C, et al. Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment. Sleep Med, 2019, 55: 74-80.
45. Cope S, Jansen JP. Quantitative summaries of treatment effect estimates obtained with network meta-analysis of survival curves to inform decision-making. BMC Med Res Methodol, 2013, 13: 147.
46. Zhou X, Du J, Liang Y, et al. The efficacy and safety of pharmacological treatments for restless legs syndrome: systemic review and network meta-analysis. Front Neurosci, 2021, 15: 751643.
47. Ahmed M, Hays R, Steven PJ, et al. Effect of gabapentin enacarbil on individual items of the international restless legs study group rating scale and post-sleep questionnaire in adults with moderate-to-severe primary restless legs syndrome: pooled analysis of 3 randomized trials. Clin Ther, 2016, 38(7): 1726-1737.
48. Avidan AY, Lee D, Park M, et al. The effect of gabapentin enacarbil on quality of life and mood outcomes in a pooled population of adult patients with moderate-to-severe primary restless legs syndrome. CNS Drugs, 2016, 30(4): 305-316.
49. Allen R, Oertel W, Walters A, et al. Relation of the international restless legs syndrome study group rating scale with the clinical global impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire. Sleep Med, 2013, 14(12): 1375-1380.
50. Ferré S, García-Borreguero D, Allen RP, et al. New insights into the neurobiology of restless legs syndrome. Neuroscientist, 2019, 25(2): 113-125.
51. Yepes G, Guitart X, Rea W, et al. Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Ann Neurol, 2017, 82(6): 951-960.
52. Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med, 2014, 15(11): 1288-1301.
53. Vellieux G, d'Ortho MP. Restless legs syndrome. Rev Med Interne, 2020, 41(4): 258-264.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of medicines for restless legs syndrome: a network meta-analysis

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