Table 1
Summary of the use of benzodiazepines in the treatment of RLS/PLMS.
| MEDICATION | AUTHOR | YEAR | # SUBJECTS | PSG | TYPE OF STUDY | DOSAGE | RLS | PLMS | PLMS AND AROUSALS | SLEEP | SIDE EFFECTS | ASSOCIATED DISEASES | FAILURE OF OTHER AGENTS |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clonazepam | |||||||||||||
| Matthews [8] | 1979 | 5 RLS with PLMS | No | OL | 1mg before bedtime | ↓ | ↓ subjectively | Not reported | ↑ subjectively | Not reported | Not reported | Not reported | |
| Read and Feest et al [9] | 1981 | 15 RLS | No | OL | 0.5 mg at 6 PM and 1/2 hr prior to hs | ↓ | Not reported | Not reported | Not reported | Lethargy at >3mg in one patient where dosage was increased* | 15 with uraemia | temazepam, chlordiazepoxide, diazepam, nitrazepam, and lorazepam | |
| Oshtory and Vijayan [10] | 1980 | 2 PLMS | Yes | OL | 1 mg before bedtime | Not reported | ↓ PSG | Not reported | ↑ PSG | Not reported | Not reported | barbiturates, diazepam, carbamazepine, tricyclic antidepressants | |
| Montagna et al [11] | 1984 | 6 RLS with PLMS | Yes | DB crossover | 1 mg at 1/2 hr before bedtime | Improvement on 4 point scale | No effect on 4 point scale | Not reported | Improvement on 4 point scale | None | Not reported | iron, flurazepam and lorazepam | |
| Rousseau and Debatisse [12] | 1985 | 2 PLMS | Yes | OL | Not reported | Not reported | ↓ PSG | Not reported | Not reported | Not reported | Not reported | Not reported | |
| Ohanna et al [13] | 1985 | 20 PLMS | Yes | OL | 0.5–2.0 mg at bedtime | Not reported | ↓ PSG | No effect | ↑ subjectively | Not reported | One patient with RLS | Not reported | |
| Peled and Lavie [14] | 1987 | 20 PLMS | Yes | DB parallel | 0.5–2.0 mg hs | Not reported | ↓ PSG | ↓ PSG | ↑ PSG | One with somnolence and one with dizziness | 1 with diabetes mellitus, 2 with mild pyramidal signs | Not reported | |
| Mitler et al [15] | 1986 | 10 PLMS | Yes | DB crossover | 1 mg hs | Not reported | No change in PLMS without arousals on PSG | ↓ PSG | ↑ PSG and improvement on 7 point scale | Not reported | 2 with RLS | Not reported | |
| Boghen [16] | 1980 | 3 RLS with PLMS | No | OL | 0.5 mg 3x day or 0.5 mg hs | ↓ | ↓ subjectively | Not reported | Not reported | None | Not reported | Not reported | |
| Boghen et al [17] | 1986 | 6 RLS | No | DB cross-over | 2 mg in divided dosages | No effect 5 point scale | Not reported | Not reported | Not reported | Somnolence in 3 patients on Clonazepam | Not reported | Not reported | |
| Montplaisir et al [18] | 1985 | 2 RLS with PLMS | Yes | OL | 0.5 mg 1 hour prior to hs | ↓ | ↓ subjectively | Not reported | Not reported | Somnolence and confusion at 4mg in one patient where dosage was increased** | Not reported | Not reported | |
| Horiguchi et al [19] | 1992 | 15 RLS with PLMS | Yes | OL | 0.5–1.5 mg at bedtime | ↓ | ↓ PSG | Not reported | ↑ subjectively | Not reported | Not reported | Not reported | |
| Edinger et al [20] | 1996 | 8 PLMS | Yes | OL | 0.5–1.0 mg | Not reported | No effect on PSG | ↓ PSG | ↑ on sleep Log and insomnia questionnaire | None | Not reported | Not reported | |
| Saletu et al [21] | 2001 | 26 ; 10 RLS, 16 PLMD | Yes | SB crossover | 1 mg | Not reported | No overall effect on PSG | No effect on PSG | ↑ PSG and sleep quality scale | Not reported | One with obstructive apnea; one with primary snoring | Not reported | |
| Manconi [22] | 2012 | 46 RLS with PLMS | Yes | SB parallel | 0.5 mg | Improvement on VAS | No effect on PSG | ↓ PSG | No effect on most parameters | Mild morning drowsiness in 2 patients | Not reported | Not reported | |
| Roshi et al [23] | 2018 | Sample size not given RLS | No | OL | 0.5 mg hs | improvement in RLS QoL | Not reported | Not reported | Not reported | Giddiness(44.4%), somnolence(33.3%), constipation(11.1%), gastritis (11.1%) | Not reported | Not reported | |
| Roshi et al [24] | 2019 | 60 RLS | No | OL | 0.5 mg hs | Improvement on IRLS | Not reported | Not reported | Not reported | Giddiness(30%), somnolence(50%), constipation and gastritis (10%) | Not reported | Not reported | |
| Triazolam | |||||||||||||
| Bonnet and Arand [25] | 1990 | 11 PLMS | Yes | DB crossover | Placebo or 0.125 mg; or 0.25 mg at 30 minutes prior to hs | Not reported | No effect on PSG | No effect on PSG | Improved by MSLT and PSG | Not reported | Not reported | Not reported | |
| Bonnet and Arand [26] | 1991 | 9 PLMS | Yes | DB crossover | 0.125 mg | Not reported | No effect on PSG | No effect on PSG | Improved by MSLT, vigilance test and PSG | None | Not reported | Not reported | |
| Doghramji et al [27] | 1991 | 15 PLMS | Yes | DB crossover | placebo or 0.25 mg or 0.50 mg | Not reported | No effect on PSG | ↓ PSG | Improved by MSLT and PSG | One subject with daytime sedative carry-over | Not reported | Not reported | |
| Alprazolam | |||||||||||||
| Scharf et al [28] | 1986 | 10 RLS | No | OL | 0.5–2.0 mg at bedtime | ↓ | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | |
| Temazepam | |||||||||||||
| Mitler et al [15] | 1986 | 10 PLMS | Yes | DB crossover | 30 mg hs | Not reported | No change in PLMS without arousal | ↓ PSG | ↑ PSG and improvement on 7 point scale | Not reported | 2 with RLS | Not reported | |
| Nitrazepam | |||||||||||||
| Moldofky et al [29] | 1986 | 13 PLMS | Yes | OL | 2.5 to 10 mg | Not reported | ↓ PSG | ↓ PSG | ↑ PSG and subjectively | One with sluggishness and impaired concentration | two with hypertension; one with stroke; one with complex partial seizures; one with leg cramps; three with end stage renal disease; two with RLS with migraine or “fibrositis” syndrome; one with iron deficiency anemia and menorrhagia; one with coronary artery disease, chronic low back and lower limb pain | Not reported | |
[i] See text for detailed description of the double blind studies including age, gender, and duration of the studies. RLS: Restless Legs Syndrome; PLMS: Periodic Limb Movements in Sleep; PLMD: Periodic Limb Movement Disorder; Arousals: defined as isolated arousals, arousals associated with PLMS or PLMS associated with arousals – check individual citations for details; OL: open label; DB = double blind; SB: single blind; hs. = bedtime; PSG: polysomnogram; CGI-S: Clinical Global Impression Severity Scale; VAS: Visual Analogue Scale; IRLS: International Restless Legs Scale; RLS QoL: Restless Legs Quality of Life scale; MSLT: Multiple Sleep Latency Test
* Only one patient had to increase the dosage to as much as 3 mg/day and they experienced extreme somnolence and only partial relief of their symptoms.
** The mother’s RLS symptoms responded to 0.5 mg 1 hour prior to hs but the RLS symptoms and PLMS of the propositus required 4 mg/day.
Figure 1
Indicates the number of studies showing benefit for each of the parameters listed for all of the studies of all of the benzodiazepines combined in Table I. An increase in Sleep and a decrease in RLS, PLMS and PLMS associated with arousals are considered benefits. RLS = Restless Legs Syndrome; PLMS = Periodic Limb Movements in Sleep; Arousals = isolated arousals, arousals associated with PLMS or PLMS associated with arousals – check individual citations for details. The order for improvement is Sleep>RLS>PLMS and arousals > PLMS. The order is the same if only blinded studies are taken into account.