Chapter 35 Additional Agents and Miscellaneous Therapies
Sedative-Hypnotics
These drugs in general, and clonazepam in particular, were among the first used and reported on (in 1979) for the treatment of restless legs syndrome (RLS).1 However, their ability to specifically alleviate RLS symptoms is controversial. At one time, they were commonly recommended for the treatment of RLS, but most RLS experts use these drugs primarily as supplementary therapy to treat the insomnia associated with RLS,2 although some patients may respond to monotherapy. The early reports of success in RLS with benzodiazepines did not use validated instruments and may have depended largely on the alleviation of sleep-related or bedtime complaints. In the modern era with more sophisticated controlled designs and validated assessments, there have been no studies with benzodiazepines and few with newer sedative-hypnotics. The majority of studies are open label and may have been contaminated by the placebo effect, which is common to RLS treatment trials using subjective measures.3 This placebo effect may account for much of the relief of any daytime symptoms attributed to the benzodiazepines. Even in the placebo-controlled trials, the marked improvement of disruptive sleep patterns due to the use of these drugs and resultant increased daytime well-being may decrease the perception of bothersome daytime RLS symptoms.
Another concern about the use of sedative-hypnotics (especially with their daytime use or with the bedtime use of long-acting ones that may carry over into the next day) is that they have a potential for worsening daytime RLS symptoms4 if they induce sedation. One study found that intravenous administration of diphenhydramine 25 mg or lorazepam 0.5 mg to 12 RLS patients who were adequately treated with dopamine agonists caused both similar and severe exacerbations of their otherwise controlled RLS symptoms.4 Further, they can increase the risk of accidents, including falls in the elderly and errors during activities that require vigilance, such as driving.
However, when choosing a sedative-hypnotic, it is generally best to select one that has a quick onset to promote sleep initiation and a relatively short half-life to prevent daytime sleepiness or drowsiness that in turn may promote increased daytime RLS symptoms (Tables 35-1 and 35-2). For chronic daily use, the nonbenzodiazepines (Table 35-2) are greatly preferred due to their decreased side effect profile and markedly decreased risks of tolerance and dependence. Much of the selection depends on clinical judgment, because there is little specific evidence to support use of the agents in RLS.
| Generic Drug Name | Half-life (hr) | Individual Dose Range (mg) |
|---|---|---|
| Ramelteon | 1 to 2.6 | 8 |
| Eszopiclone | 6 | 1 to 3 |
| Zaleplon | 1 | 10 to 20 |
| Zolpidem | 2.5 | 5 to 10 |
| Zolpidem slow release | 2.8 | 6.25 to 12.5 |
The European Federation of Neurological Societies (EFNS) task force recommendation for the use of sedative-hypnotics is that clonazepam should be considered as probably effective for improving symptoms in primary RLS when given at 1 mg before bedtime but also probably as ineffective when given at four doses throughout the day. However, any of the benzodiazepines that are approved for sleep (see Table 35-1) and all of the nonbenzodiazepine hypnotics (see Table 35-2) can be used for their approved indication to aid sleep, which is often necessary for the RLS population.
Benzodiazepines
This group comprises several drugs that share similarities and are marketed either as a hypnotic for inducing sleep or to treat anxiety (see Table 35-1). Despite being approved and marketed only as a sedative, some of these drugs may be suitable for use as a hypnotic. The discussion below will review the literature on the use of these medications for treating RLS.
Clonazepam
Clonazepam was used, beginning in 1979, to treat RLS. It was probably introduced into RLS because of the association with PLMS, then usually termed nocturnal myoclonus: at that time, clonazepam was one of the mainstays of general myoclonus treatment. The first reports were just small cases series.1,5 The first double-blind crossover trial of clonazepam was a comparative trial against vibration in six subjects.6 Clonazepam, but not vibration, was more effective than placebo and was also well tolerated with significant adverse effects.6 However, the next study, also a placebo-controlled double blind crossover study, did not find clonazepam to be more effective than placebo.7 As a result of these mixed results, the EFNS recommendation for clonazepam was that it is probably effective for RLS when given at 1 mg before bedtime but was probably ineffective when given at 4 doses throughout the day.8
The concern with this drug is that it has a 30- to 40-hour half-life, which may easily result in next-day sedation, especially when taken for several nights consecutively. Some studies have suggested that this adverse effect may not be clinically significant for many patients, including the elderly.9 This daytime sedation is often not apparent to the patient, especially compared with their previous RLS-induced, sleep-deprived state. As other shorter-acting sedative-hypnotics have been shown to be effective for RLS (see later), there are alternatives that may be safer and also inexpensive. Tolerance and dependence are real risks with benzodiazepines, although this may not be a universal finding.9
Alprazolam
An open-label study examined alprazolam at 0.5 mg to 1 mg at bedtime given to 10 subjects with RLS.10 Eight of 10 patients were said to improve on alprazolam. One patient stated that taking 0.5 mg of the drug before going to the theater would provide her with relief throughout the entire evening. Alprazolam, although not approved as a hypnotic, can still be a reasonable choice for that purpose. Its onset is rapid and has a short to medium-duration half-life of 6 to 12 hours that at lower doses may avoid daytime sedation. Similar to other benzodiazepines, tolerance and dependence may occur with chronic daily use.
Triazolam
There is one report of triazolam 0.25 mg taken at bedtime helping one patient with RLS for 6 months.11 This patient stopped the drug and experienced recurrence of her symptoms within 48 hours. There are also several articles demonstrating the benefits of triazolam12–14 for PLM. These studies demonstrated improvements in sleep architecture by increasing total sleep time, decreasing the number of awakenings and arousals, decreasing stage 1 sleep, while increasing stage 2 sleep and increasing sleep efficiency. Additionally, daytime sleepiness was diminished. Although the number of PLM was not decreased, there was a major decline in the number of arousals and awakenings from the PLM. Triazolam has a very quick onset of action and a very short half-life of 1.5 to 5.5 hours that limits next-day drowsiness. However, use of this drug has been associated with a significant degree of retrograde amnesia and rebound insomnia, which limit enthusiasm for its use.
Temazepam
No studies have yet evaluated this drug for RLS. However, one study has shown the efficacy of temazepam for PLS.15 Improvements in sleep similar to those noted above for triazolam were also observed with temazepam. This drug has an onset after 45 to 60 minutes with a half-life of about 9 to 12 hours. No studies have yet been done in RLS.
Related posts:
Clinical Science of Restless Legs Syndrome
Introduction: Comorbid Disorders and Special Populations
Differential Diagnosis of Restless Legs Syndrome
Restless Legs Syndrome in Neurological Disorders
Spinal Cord, Dopamine, Opiates, and Restless Legs Syndrome
Restless Legs Syndrome Morbidity: Sleep and Quality of Life
