Gabapentin for Restless Legs Syndrome: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Zibin ,  WU Yuan , LIU Xiaofei , LIU Yun , MA Meigang , LIU Qiudi , TAN Minghui

Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China;

Corresponding author：

WU Yuan, Email: wuyuan90@126.com

Keywords：

Gabapentin; Anticonvulsants; Restless legs syndrome; Systematic review; Randomized controlled trial; Meta-analysis

DOI：

10.7507/1672-2531.20120118

Video：

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Objective To assess the efficacy and safety of gabapentin for restless legs syndrome (RLS).
Methods Such databases as PubMed, EMbase, CENTRAL and CBM were searched for collecting the randomized controlled trials (RCTs) on the efficacy and/or tolerability of gabapentin for restless legs syndrome. Methodological quality of the trials was evaluated using the Cochrane risk-of-bias criteria, and meta-analysis was carried out using RevMan 5.1.
Results Seven RCTs involving 1 163 patients which met the criteria were included, of which 4 were placebo parallel controlled trials and 3 were placebo cross-over trials. The outcomes of meta-analysis suggested that a) As to the change of RLS severity based on IRLSSG score, gabapentin was superior to placebo in alleviating the severity of RLS (MD= –3.24, 95%CI –4.40 to –2.09, P lt;0.000 01); b) As to the response rate based on investigator-rated CGI-I scale, it was higher in the gabapentin group (77%) compared with that in the placebo group (50%) (RR=1.81, 95%CI 1.54 to 2.11, P lt;0.000 01); c) As to quality of sleep, gabapentin was superior to placebo in reducing sleep disturbance (MD= –11.31, 95%CI –14.46 to –8.16), assuring quality of sleep (MD= 0.27, 95%CI 0.10 to 0.44) and alleviating daytime somnolence (MD= –3.96, 95%CI –6.42 to –1.50); and d) As to the RLS pain score, gabapentin was better in relieving pain compared with placebo (MD= –0.97, 95%CI –1.47 to –0.47). In addition, main side effects were somnolence (3.1% to 26.5%) and dizziness (2.1% to 19.5%), and there was a significant difference between two groups.
Conclusion Gabapentin can effectively alleviate RLS patients’ condition, improve quality of sleep, relieve pain and show good tolerability.

Citation： CHEN Zibin,WU Yuan,LIU Xiaofei,LIU Yun,MA Meigang,LIU Qiudi,TAN Minghui. Gabapentin for Restless Legs Syndrome: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2012, 12(6): 727-734. doi: 10.7507/1672-2531.20120118 Copy

1.	Willis T. The London practice of physick. London: Thomas Basset and William Crook. 1685.
2.	Ekbom A. Restless legs: A clinical study. Acta Med Scand, 1945, 158(suppl): 1-123.
3.	Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med, 2003, 4(2): 101-119.
4.	Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med, 2005, 165(11): 1286-1292.
5.	Nomura T, Inoue Y, Kusumi M, et al. Prevalence of restless legs syndrome in a rural community in Japan. Mov Disord, 2008, 23(16): 2363-2369.
6.	Tan EK, Seah A, See SJ, et al. Restless legs syndrome in an Asian population: A study in Singapore. Mov Disord, 2001, 16(3): 577-579.
7.	Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med, 2004, 5(3): 237-246.
8.	Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol, 2005, 4(8): 465-475.
9.	Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord, 2008, 23(16): 2267-2302.
10.	Conti CF, Oliveira MM, Valbuza JS, et al. Anticonvulsants to treat idiopathic restless legs syndrome: systematic review. Arq Neuropsiquiatr, 2008, 66(2b): 431-435.
11.	Walters AS, Lebrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med, 2003, 4(2): 121-132.
12.	National Institute of Medtal Health. Early Clinical Drug Evaluation Unit (ECDEU). Clinical Global Impressions. In: Guy W, ed ECDEU Assessment Manual for Psychopharmacology Rockville, MD: NIMH, USA, 1976, 218-222.
13.	Higgins J, Altman DG. Assessing risk of bias in included studies. In: Cochrane Handbook for Systematic Reviews of Interventions Version 510 [updated March 2011], 2011, Chapter 8.
14.	Micozkadioglu H, Ozdemir FN, Kut A, et al. Gabapentin versus levodopa for the treatment of restless legs syndrome in hemodialysis patients: An open-label study. Renal Failure, 2004, 26(4): 393-397.
15.	Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. American Journal of Kidney Diseases, 2001, 38(1): 104-108.
16.	石强, 黄旭升, 崔芳, 等. 加巴喷丁治疗不安腿综合征的疗效观察. 中国临床神经科学, 2008, 16(6): 627-629.
17.	Happe S, Sauter C, Klosch G, et al. Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology, 2003, 48(2): 82-86.
18.	Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol, 1997, 20(2): 148-151.
19.	Saletu M, Anderer P, Saletu-Zyhlarz GM, et al. Comparative placebo-controlled polysomnographic and psychometric studies on the acute effects of gabapentin versus ropinirole in restless legs syndrome. Journal of Neural Transmission, 2010, 117(4): 463-473.
20.	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.
21.	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.
22.	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.
23.	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. Clinical Neuropharmacology, 2009, 32(6): 311-320.
24.	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.
25.	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.
26.	Garcia-Borreguero D, Larrosa O, De La Llave Y, et al. Treatment of restless legs syndrome with gabapentin: A double-blind, cross-over study. Neurology, 2002, 59(10): 1573-1579.
27.	Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology, 1996, 47(6): 1435-1441.
28.	Pugsley TA, Whetzel SZ, Dooley DJ. Reduction of 3,4-diaminopyridine-induced biogenic amine synthesis and release in rat brain by gabapentin. Psychopharmacology (Berl), 1998, 137(1): 74-80.
29.	Fulda S, Wetter TC. Dopamine agonists for the treatment of restless legs syndrome. Expert Opin Pharmacother, 2005, 6(15): 2655-2666.
30.	Telstad W, Sorensen O, Larsen S, et al. Treatment of the restless legs syndrome with carbamazepine: a double blind study. Br Med J (Clin Res Ed), 1984, 288(6415): 444-446.
31.	Lundvall O, Abom PE, Holm R. Carbamazepine in restless legs. A controlled pilot study. European Journal of Clinical Pharmacology, 1983, 25(3): 323-324.
32.	Eisensehr I, Ehrenberg BL, Solti SR, et al. Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid: A randomized, placebo-controlled, double-blind, cross-over study. Journal of Neurology, 2004, 251(5): 579-583.
33.	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.
34.	Partinen M, Hirvonen K, Jama L, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study. Sleep Med, 2006, 7(5): 407-417.
35.	Bliwise DL, Freeman A, Ingram CD, et al. Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome. Sleep Med, 2005, 6(2): 141-147.
36.	Hogl B, Garcia-Borreguero D, Kohnen R, et al. Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study. J Neurol, 2010, 257(2): 230-237.

1. Willis T. The London practice of physick. London: Thomas Basset and William Crook. 1685.
2. Ekbom A. Restless legs: A clinical study. Acta Med Scand, 1945, 158(suppl): 1-123.
3. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med, 2003, 4(2): 101-119.
4. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med, 2005, 165(11): 1286-1292.
5. Nomura T, Inoue Y, Kusumi M, et al. Prevalence of restless legs syndrome in a rural community in Japan. Mov Disord, 2008, 23(16): 2363-2369.
6. Tan EK, Seah A, See SJ, et al. Restless legs syndrome in an Asian population: A study in Singapore. Mov Disord, 2001, 16(3): 577-579.
7. Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med, 2004, 5(3): 237-246.
8. Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol, 2005, 4(8): 465-475.
9. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord, 2008, 23(16): 2267-2302.
10. Conti CF, Oliveira MM, Valbuza JS, et al. Anticonvulsants to treat idiopathic restless legs syndrome: systematic review. Arq Neuropsiquiatr, 2008, 66(2b): 431-435.
11. Walters AS, Lebrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med, 2003, 4(2): 121-132.
12. National Institute of Medtal Health. Early Clinical Drug Evaluation Unit (ECDEU). Clinical Global Impressions. In: Guy W, ed ECDEU Assessment Manual for Psychopharmacology Rockville, MD: NIMH, USA, 1976, 218-222.
13. Higgins J, Altman DG. Assessing risk of bias in included studies. In: Cochrane Handbook for Systematic Reviews of Interventions Version 510 [updated March 2011], 2011, Chapter 8.
14. Micozkadioglu H, Ozdemir FN, Kut A, et al. Gabapentin versus levodopa for the treatment of restless legs syndrome in hemodialysis patients: An open-label study. Renal Failure, 2004, 26(4): 393-397.
15. Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. American Journal of Kidney Diseases, 2001, 38(1): 104-108.
16. 石强, 黄旭升, 崔芳, 等. 加巴喷丁治疗不安腿综合征的疗效观察. 中国临床神经科学, 2008, 16(6): 627-629.
17. Happe S, Sauter C, Klosch G, et al. Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology, 2003, 48(2): 82-86.
18. Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol, 1997, 20(2): 148-151.
19. Saletu M, Anderer P, Saletu-Zyhlarz GM, et al. Comparative placebo-controlled polysomnographic and psychometric studies on the acute effects of gabapentin versus ropinirole in restless legs syndrome. Journal of Neural Transmission, 2010, 117(4): 463-473.
20. 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.
21. 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.
22. 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.
23. 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. Clinical Neuropharmacology, 2009, 32(6): 311-320.
24. 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.
25. 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.
26. Garcia-Borreguero D, Larrosa O, De La Llave Y, et al. Treatment of restless legs syndrome with gabapentin: A double-blind, cross-over study. Neurology, 2002, 59(10): 1573-1579.
27. Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology, 1996, 47(6): 1435-1441.
28. Pugsley TA, Whetzel SZ, Dooley DJ. Reduction of 3,4-diaminopyridine-induced biogenic amine synthesis and release in rat brain by gabapentin. Psychopharmacology (Berl), 1998, 137(1): 74-80.
29. Fulda S, Wetter TC. Dopamine agonists for the treatment of restless legs syndrome. Expert Opin Pharmacother, 2005, 6(15): 2655-2666.
30. Telstad W, Sorensen O, Larsen S, et al. Treatment of the restless legs syndrome with carbamazepine: a double blind study. Br Med J (Clin Res Ed), 1984, 288(6415): 444-446.
31. Lundvall O, Abom PE, Holm R. Carbamazepine in restless legs. A controlled pilot study. European Journal of Clinical Pharmacology, 1983, 25(3): 323-324.
32. Eisensehr I, Ehrenberg BL, Solti SR, et al. Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid: A randomized, placebo-controlled, double-blind, cross-over study. Journal of Neurology, 2004, 251(5): 579-583.
33. 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.
34. Partinen M, Hirvonen K, Jama L, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study. Sleep Med, 2006, 7(5): 407-417.
35. Bliwise DL, Freeman A, Ingram CD, et al. Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome. Sleep Med, 2005, 6(2): 141-147.
36. Hogl B, Garcia-Borreguero D, Kohnen R, et al. Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study. J Neurol, 2010, 257(2): 230-237.

Chinese Journal of Evidence-Based Medicine

Gabapentin for Restless Legs Syndrome: A Systematic Review

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