Objective: To evaluate the efficacy and safety of benzodiazepines (BZD) as treatment for Restless Legs Syndrome (RLS), compared to placebo or other drugs.

Background: RLS is a neurological condition that causes a strong urge to move the legs, typically in the evening when lying down[1-4]. The prevalence is estimated to be up to 15% of the population[5]. First-line treatments for RLS are anticonvulsants or dopamine agonists/precursors[2,6]. BZD are sometimes used because of their sedative effect, although there is little evidence supporting this practice[6,7].

Method: We systematically reviewed PUBMED, EMBASE and CENTRAL databases for RCTs and controlled observational studies with RLS patients treated with BZD. Main outcomes were sleep quality, quality of life, periodic leg movements (PLM) and adverse events (AE). Statistical analysis was performed in R 4.3.2[8] with the meta package[9]. Heterogeneity was examined with I2. Crossover studies were treated as if they were parallel-group trials.

Results: 4 studies were included in the review (145 patients)[10-13], 3 in the meta-analysis (26 patients)[10-12]. One was an RCT comparing clonazepam to nortriptyline [13], the others were crossover trials of clonazepam versus placebo for RLS[10-12]. In the pooled analysis, clonazepam was associated with an improvement in sleep quality scales (SMD -0.86; 95% CI -1.53 – -0.19; p=0.01; I2=4%) when compared to placebo [figure1][10-12]. The studies reported significant improvement in leg dysaesthesia[11], number of awakenings and sleep time[12], but not in leg jerking[11] or PLM[12]. Clonazepam was superior to nortriptyline regarding sleep quality, mood and day-to-day activities, improving RLS patients’ quality of life[13]. As for AE, sleepiness[10,12], leg paresthesia, myoclonic jerks, fatigue[10], vertigo, constipation and gastritis[12] were reported in the BZD groups.

Conclusion: Our results suggest that clonazepam is an alternative in the treatment of patients with RLS, improving especially sleep quality. Due to treating crossover studies as parallel-groups, our findings were affected by unit-of-analysis issues, possibly resulting in wider confidence intervals. Furthermore, the number of analyzed patients was small and no studies compared BZD to first-line treatments for RLS, reinforcing the need for new, larger RCTs with BZD, assessing beneficial and side effects.

Figure 1 – Sleep Quality Scales

References: [1] Klingelhoefer L, Bhattacharya K, Reichmann H. Restless legs syndrome. Clinical Medicine [Internet]. 2016 Aug 1;16(4):379–82. Available from:
[2] Alan Christmann Fröhlich, Alan Luiz Eckeli, Bacelar A, Dalva Poyares, Daniela Vianna Pachito, Fernando Gustavo Stelzer, et al. Brazilian consensus on guidelines for diagnosis and treatment for restless legs syndrome. 2015 Mar 1;73(3):260–80.
[3] Ekbom K, Ulfberg J. Restless legs syndrome. Journal of Internal Medicine. 2009 Nov;266(5):419–31. ‌
[4] Symvoulakis E, Anyfantakis D, Lionis C. Restless legs syndrome: literature review. Sao Paulo Medical Journal. 2010 May;128(3):167–70.
[5] Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: A synthesis of the literature. Sleep Medicine Reviews. 2012 Aug;16(4):283–95.
[6] Silber MH, Buchfuhrer MJ, Earley CJ, Koo BB, Manconi M, Winkelman JW, et al. The Management of Restless Legs Syndrome: An Updated Algorithm. Mayo Clinic Proceedings [Internet]. 2021 Jul 1;96(7):1921–37. Available from:
[7] Carlos K, Prado GF, Teixeira CD, Conti C, de Oliveira MM, Prado LB, et al. Benzodiazepines for restless legs syndrome. Cochrane Database of Systematic Reviews. 2017 Mar 20;
[8] R Core Team (2023). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. .
[9] Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Mental Health. 2019 Nov;22(4):153–60.
[10] Boghen D, Lamothe L, Elie R, Godbout R, Montplaisir J. The Treatment of the Restless Legs Syndrome with Clonazepam: A Prospective Controlled Study. Can j neurol sci. 1986 Aug;13(3):245–7.
[11] Montagna P, Bianchi LS, Zucconi M, Cirignotta F, Lugaresi E. Clonazepam and vibration in restless legs syndrome. Acta Neurologica Scandinavica. 1984 Jun;69(6):428–30.
[12] Saletu M, Anderer P, Saletu-Zyhlarz G, Prause W, Semler B, Zoghlami A, et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. European Neuropsychopharmacology. 2001 Apr;11(2):153–61.
[13] Roshi, Tandon V, Mahajan A, Sharma S, Khajuria V. 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. J Mid-life Health. 2018;9(3):135.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/benzodiazepines-in-the-management-of-restless-legs-syndrome-a-systematic-review-and-meta-analysis/