Additional Agents and Miscellaneous Therapies

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Chapter 35 Additional Agents and Miscellaneous Therapies

Mark J. Buchfuhrer, Wayne A. Hening

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 symptoms ⁴ 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, the real goal of physicians is to make patients feel better. If these drugs accomplish this goal for RLS sufferers, they should be considered, especially when other drugs have not been helpful. Furthermore, a significant group of RLS sufferers state that the sedative-hypnotic drugs relieve their symptoms.

It is not uncommon for long-time RLS sufferers to have continued insomnia even after their symptoms have been resolved by treatment. After years of not sleeping well, they typically develop a “conditioned insomnia.” The use of sedative-hypnotic drugs may be invaluable to break this poor sleep cycle. These drugs can markedly decrease awakenings and stage 1 sleep that occur from periodic limb movements (PLMS) and are so common in RLS sufferers, which may be another benefit from their use

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.

TABLE 35-1 Benzodiazepines (Hypnotics and Sedatives)

TABLE 35-2 Nonbenzodiazepine Hypnotics

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

Clonazepam is a readily available and inexpensive drug and as such has a particular physician following for treating RLS. As noted earlier, it clearly resolves the insomnia associated with RLS and improves well-being in people who were suffering before treatment.

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.

Nonbenzodiazepines

Most sleep specialists prefer using this class of drugs for treating insomnia. They have short half-lives and a limited degree of dependence or tolerance. Of course, these drugs are not for everyone as they do have their own side effect profile. There is only one study on RLS with zolpidem that is discussed below. However, any of these drugs may be beneficial to help RLS patients fall asleep whether or not the insomnia is due to RLS symptoms.

Zolpidem

This drug was studied for RLS in one open-label prospective trial on eight subjects who were unresponsive or could not tolerate L-dopa and benzodiazepines.¹⁶ All patients were reported to have complete relief of their RLS symptoms within an average of 4 days of starting zolpidem at 10 mg that lasted 12 to 30 months with no relapses or side effects. Two patients stopped their medication after 1 year of treatment and had their symptoms return, then go away again with re-institution of zolpidem. Zolpidem has a very quick onset of action and a short half-life of 2.5 hours, which ensures that most patients will not experience daytime sleepiness. It has been associated with abnormal sleep-related behaviors such as sleep walking, talking, or sleep-related eating disorders¹⁷ but otherwise has been well tolerated. There is a controlled-release version of this drug that increases the half-life and releases some of the drug immediately, while the rest is released later in the sleep period to help maintain sleep.

Other Sedative-Hypnotic Agents

None of the other nonbenzodiazepine hypnotics has been studied for activity and tolerability in RLS. For those who have problems with sleep maintenance or obtaining sufficient sleep time, eszopiclone with its longer half-life of 6 hours may be more appropriate than zolpidem. On the other hand, those who feel the residual sedation in the morning may benefit from the shorter half-life (1 hour) of zaleplon. Due to its very short half-life, patients can take zaleplon for their middle of the night awakenings and not wake up sleepy a few hours later. Ramelteon is very different from all the other hypnotic drugs discussed earlier. It does not act on the GABA receptors that help promote sleep but rather on the melatonin receptors. This drug, which has relatively few side effects, is indicated for sleep-onset insomnia, because its effects on improving sleep maintenance are much less pronounced.¹⁸ It has not yet been determined how well this drug works in comparison with the more traditional hypnotic drugs for both insomnia and RLS.

Other Oral Medications

These other drugs do not fit it into the four major categories of drugs that are commonly used to treat RLS. In addition, there is very little literature or experience to support the use of these other drugs. However, in cases where the standard drugs have not been effective or cannot be tolerated, these drugs may be considered.

Clonidine

This drug, which stimulates α-adrenoceptors in the brainstem, is approved in the United States for treating hypertension and was first used for RLS in 1985.¹⁹ Several other reports have described the use of clonidine for treating primary RLS²⁰^–²² with one 2-week double-blind trial.²³ This double-blind study started their subjects on 0.1 mg of clonidine twice daily (2 hours before symptoms generally occur and again at bedtime) and then titrated by 0.1 mg every 1 to 2 days until symptoms were relieved or a maximum of 1 mg/day. Clonidine was found to be effective in relieving the leg sensations and morning drowsiness. Sleep latency was decreased (likely due to the sedative effects of the drug); however, sleep time, sleep efficiency, the number of PLMS, and arousals or awakenings were not improved. Side effects include dry mouth, decreased cognition and libido, lightheadedness, sleepiness, and headache.

Due to the lack of general experience with this drug, it might be dosed according to the double-blind study.²³ Clonidine may be a reasonable therapy for people with RLS who also have hypertension. In addition, for those who are intolerant of this drug by the oral route, some may benefit from the newer transdermal patch, which avoids the gastrointestinal system and may produce more steady serum drug levels. The EFNS has indicated that clonidine is probably effective (class B) at reducing symptoms and sleep latency in primary RLS in the short term.⁸

Amantadine

Amantadine is approved in the United States for use in Parkinson’s disease, for the prophylaxis of influenza A, and for drug-induced extrapyramidal reactions. The exact mechanism of action of this drug for Parkinson’s disease or RLS is unknown but may involve increasing the synthesis or release of dopamine or decreasing presynaptic reuptake of dopamine. After oral administration, amantadine reaches peak plasma concentration in about 3 hours, has a half-life of about 17 hours, and is excreted unchanged though the kidneys. Only one study has examined the use of amantadine for treating RLS.²⁴ This open-label trial treated 21 patients with amantadine, often as an add-on medication, starting at 100 mg/day, increasing to a maximum of 300 mg/day until symptoms were relieved or intolerable side effects were experienced. Eleven of the patients responded to the drug at a mean dose of 227 mg/day with 6 complete responders. The most common side effects were drowsiness, fatigue, and insomnia (similar to dopaminergic medications) and only 2 subjects stopped the drug due to these side effects. This drug may provide dopaminergic enhancement for subjects who cannot tolerate agonists or levodopa.

Other Oral Agents Mentioned in the Literature

β-Blockers: Propranolol

In 1967, one investigator reviewed 40 cases of RLS found in 600 of his Parkinson’s disease patients. Based on his experience, he commented that 5 to 10 mg of the β-blocker propranolol taken at dinner and if needed before bedtime worked well for RLS both therapeutically and prophylactically.²⁵ Two other cases reports also reported efficacy in RLS.^26,²⁷ Other experience is lacking, but β-blockers have also been used for treatment of akathisia, which can resemble RLS.²⁸

Vitamins

Vitamin B₁₂ and folate were reported to benefit RLS in a few uncontrolled open case series.²⁹^–³¹ Fifteen patients with RLS and other neurological disorders in an open-label trial responded to folic acid at doses of 1.25 to 30 mg/day.³¹ Because folic acid deficiency has been noted in pregnant women with RLS,³² it may be important to be sure such patients receive folic acid supplements.

Two reports of case series found that vitamin E could benefit RLS.^33,³⁴ However, there are no recent studies to support this vitamin’s use.

Minerals

Iron treatment is a potentially important treatment for RLS and is discussed in Chapter 34. The other mineral studied for RLS, magnesium, was reported to be effective in one open-label study,³⁵ even though the subjects were not all magnesium deficient.

Other Routes for Treatment, Surgical, and Additional Approaches to Restless Legs Syndrome

Transdermal Treatment

As discussed in Chapter 31, two agonists have been formulated in patches—rotigotine, a nonergot agonist,³⁶ and lisuride, an ergot derivative—that may not have same risk of fibrotic complications as other ergot-derived agonists.³⁷ Clonidine is also available in a transdermal formulation³⁸ as are some opioids, such as fentanyl.³⁹ The advantages of this formulation is that it both avoids the oral route and generally delivers a fairly constant drug over a period of a day or more. The major disadvantage—cutaneous skin reactions⁴⁰—is a relatively unique adverse event. Although it can be fairly common in RLS treatment, it is not usually a reason for discontinuing treatment in therapeutic trials.³⁶ Other dopaminergic side effects tend to be comparable with those of oral agonists with transdermal agonist treatment.³⁶

Subcutaneous Injection

The mixed dopamine and opioid agonist apomorphine has been reported beneficial in pilot studies of RLS.⁴¹^–⁴³ The advantages of this system include its usefulness when oral input is not possible and its rapid onset of action; its disadvantage is its brief duration of action, requiring frequent repeated injections. An oral formulation may be developed.

Intramuscular Injection

Iron is available for intramuscular injection but has not been used for RLS. Various opioids can also be injected. Botulinum toxin type A, which is derived from the exotoxin produced by Clostridium botulinum type A, is approved in the United States for use in the treatment of cervical dystonia in adults, severe primary axillary hyperhidrosis, strabismus, and blepharospasm associated with dystonia and for cosmetic treatment of wrinkles. In one study performed on this drug for RLS, it was given intramuscularly to three patients who were ineligible for oral therapy.⁴⁴ Injections were given at the sites of their RLS symptoms and improvement was noted within a few days. The duration of this effect appeared to be about 12 weeks when patients would get reinjected and continue to respond to this therapy. No adverse effects were noted with treatment. This unique treatment of RLS clearly needs further investigation before being recommended. In fact, there are some anecdotal cases of exacerbating RLS with this treatment.

Epidural and Intrathecal Delivery

There is one report of an emergent treatment of severe, intractable RLS “status” with epidural delivery of morphine ⁴⁵ and two cases treated with intrathecal morphine and bupivacaine.⁴⁶ These routes may offer additional complications, such as meningitis, local infection, or hemorrhage, but have the advantages in delivering much smaller doses that can be better tolerated because they are more exactly targeted. Implanted pumps can deliver regular doses. They may be explored in the future for severe cases, particularly those which have developed intractable augmentation on dopaminergics.

Nerve, Spinal Cord, and Deep Brain Stimulation

One case report found that RLS resolved after vagal nerve stimulation,⁴⁷ an approved treatment for epilepsy,⁴⁸ but also for pain,⁴⁹ which may be more relevant to RLS. Anecdotal reports have suggested that spinal cord stimulation may benefit RLS, but there are no published reports on this. After an initial report of improvement of RLS with an ablative pallidotomy,⁵⁰ there have been a number of reports of changes in RLS with deep brain stimulation. These have not been consistent. RLS was improved by pallidal stimulation⁵¹ and subthalamic nucleus (STN) stimulation⁵² in reports of patients with comorbid movement disorders and RLS. In one study, Parkinson’s disease patients after STN stimulator implantation had an emergence of RLS symptoms,⁵³ but this may have been due to reduced dopaminergic medication. RLS has been associated with essential tremor,⁵⁴ but thalamic stimulation (VIM) for essential tremor has been reported not to benefit comorbid RLS symptoms.⁵⁵

Other Surgical Approaches

There was one initial report on sclerotherapy as benefiting almost all treated RLS patients with varicose veins,⁵⁶ although repeated treatments were sometimes required and benefit was transient for some. However, that report did not provide clear diagnostic criteria for RLS and a later study suggested that RLS symptoms may not be common in varicose veins,⁵⁷ raising questions whether the varicose vein subjects in the sclerotherapy trial did have RLS.

Other surgical approaches have been used to alleviate underlying disorders that could cause secondary RLS—such as kidney transportation for renal failure—and not for idiopathic RLS.

References

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2. Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79:916-922.

3. Fulda S, Wetter TC. Where dopamine meets opioids: A meta-analysis of the placebo effect in RLS treatment studies. Brain. 2008;131:902-917.

4. Allen RP, Lesage S, Earley CJ. Anti-histamines and benzodiazepines exacerbate daytime restless legs syndrome symptoms [abstract]. Sleep. 2005;28:A279.

5. Boghen D. Successful treatment of restless legs with clonazepam. Ann Neurol. 1981;8:341.

6. Montagna P, de Bianchi LS, Zucconi M, et al. Clonazepam and vibration in restless leg syndrome. Acta Neurol Scand. 1984;69:428-430.

7. Boghen D, Lamothe L, Elie R, et al. The treatment of the restless legs syndrome with clonazepam: A prospective controlled study. Can J Neurol Sci. 1986;13:245-247.

8. Vignatelli L, Billiard M, Clarenbach P, et al. EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep. Eur J Neurol. 2006;13:1049-1065.

9. Schenck CH, Halfaker BA, Mahowald MW. Sustained benefit and low risk of major adverse effects during long-term nightly benzodiazepine and/or opiate treatment of injurious parasomnias, restless legs/periodic limb movement disorder and insomnia in 121 adult patients. Sleep Res. 1994;24:81.

10. Scharf MB, Brown L, Hirschowitz J. Possible efficacy of alprazolam in restless leg syndrome. Hillside J Clin Psychiatry. 1986;8:214-223.