Management of Restless Legs Syndrome and Periodic Leg Movement Disorder
Maryann C. Deak
John W. Winkelman
TREATMENT OF RESTLESS LEGS SYNDROME
Several factors should be considered before deciding if treatment is necessary in a patient with restless legs syndrome (RLS) and what specific treatment modality is most appropriate. As symptomatic improvement is the goal of treatment in RLS, it is important to review symptoms of RLS, which can be divided into two broad categories. One category of symptoms includes the four core sensory symptoms of RLS, which are required for diagnosis (see Chapter 6). The other category includes the secondary consequences of RLS (i.e. the impact on sleep). One epidemiological study, which utilized questionnaires in a primary care setting, found that sleeprelated symptoms were the most troublesome symptoms reported by patients with RLS (1). In addition, 88.4% of RLS sufferers reported at least one sleep-related symptom, including inability to fall asleep, inability to stay asleep, or disrupted sleep. Potential long-term consequences of RLS are not currently the basis for treatment decisions, because a causal link has not been established between RLS and these potential consequences. However, RLS does have several disease correlates including quality of life, mood symptoms, and cardiovascular disease (2), which are potentially related to sleep disturbance in RLS. These disease correlations may become more important in the future when making treatment decisions.
In clinical research trials, RLS symptoms are often quantified using the International Restless Legs Syndrome rating scale (IRLS), which is a validated instrument for assessing symptom severity that has also been used as a therapeutic outcome measure (Table 12.1) (3,4). The scale gauges the severity of discomfort from RLS symptoms, the frequency of symptoms, as well as the impact on sleep, daytime fatigue/sleepiness, mood symptoms and work/home life. Often, subjects included in clinical research trials fall into the category of moderate to severe RLS based on the IRLS. Although treatment decisions in clinical practice are different from inclusion criteria for clinical trials, the IRLS does highlight important questions that should be explored with patients in clinical practice. Because the treatment modalities for RLS can only provide relief of symptoms, rather than resolution of the disorder, treatment should be initiated only when the benefits of treatment are sufficient to outweigh potential side effects.
After it is determined that a patient is an appropriate candidate for treatment, a specific treatment modality should be chosen, and it should be determined how frequently treatment should be administered (Table 12.2). Ample consideration must first be given to possible secondary causes of RLS, such as iron deficiency and renal failure. If identified, factors contributing to secondary RLS should be treated whenever possible (e.g., iron replacement). Once primary RLS is confirmed, the choice of pharmacologic versus nonpharmacologic therapy should be made, as well as the selection of a specific drug if pharmacologic therapy is preferred. The frequency of symptoms must be considered, as some patients may only require treatment on an as-needed basis, rather than daily treatment. Patients without frequent symptoms are more likely to be treated effectively with nonpharmacologic therapy than those with frequent symptoms. It is important to keep in mind that the appearance of RLS symptoms is closely tied to a patient’s activity level. Adjustment in activity patterns may be an effective treatment or adjunctive treatment for RLS. The quality of the patient’s discomfort, in addition to the presence of comorbidities may contribute to the choice of a pharmacologic agent. For example, patients who complain of a painful quality to their symptoms or who have RLS symptoms compounded by arthritic or neuropathic pain may benefit from an agent such as gabapentin as a first-line agent, rather than a dopamine agonist (5). Finally, in distinction to most other medical disorders, RLS has a relatively predictable time of onset for an individual patient. The provider must attempt to obtain an accurate idea of the time of symptom onset, as the administration of pharmacologic or nonpharmacologic therapies should be timed accordingly.
TABLE 12.1 International Restless Legs Syndrome Rating Scale (IRLS) | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||
TABLE 12.2 Issues to Consider When Making RLS Treatment Decisions | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Primary RLS
Pharmacologic Therapy (Table 12.3)
Although RLS was depicted as early as the 1670s, it was not until the 1940s that Ekbom extensively described the syndrome and coined the term “restless legs syndrome”(6,7). Similarly, various treatment modalities were described beginning as early as the 1680s. In 1982, dopamine was discovered as a treatment modality for RLS, with a paper that described the effectiveness of levodopa in combination with benserazide for treatment of RLS (8). Today, dopaminergic agents are the beststudied pharmacological options and have become the first-line treatment for RLS (9,10). Alternatives to dopaminergic medications include antiepileptic medications, opioids, benzodiazepines, and iron therapy.
Dopaminergic Agents
Levodopa. Levodopa is a short-acting medication, which reaches peak plasma concentration between 0.5 and 2 hours and has a half-life of 1 to 3 hours. Levodopa has a complicated metabolism, and it is partially metabolized by the gastrointestinal tract, kidneys, and liver, but it is primarily excreted through the renal system. The range of doses of levodopa with carbidopa or benserazide used for treatment of RLS is between 100/25 mg and 200/50 mg. It is usually administered about 30 minutes prior to symptom onset. If immediate release levodopa is used, dosing may need to be repeated during the night.
Although levodopa was the first dopaminergic agent used for the treatment of RLS, there are few double-blind, placebo-controlled trials that examine the effectiveness of levodopa in the treatment of primary RLS (11, 12 and 13). Such studies noted improvements in sleep duration (12) and quality (12,13), quality of life (12), severity of RLS symptoms (12), and periodic limb movements of sleep (11, 12 and 13) compared to placebo. Levodopa was well tolerated during short-term studies of levodopa/benserazide or levodopa/carbidopa (12,14). Common side effects in short-term studies included gastrointestinal symptoms, muscle weakness, somnolence, and headache (14).
When levodopa was tested in long-term trials, there was a high incidence of augmentation, with rates ranging from 35% to 82% (15,16). Augmentation, which will be discussed in greater detail later in the text, is defined by a shift of symptom onset earlier than the typical pretreatment time of onset of symptoms and/or increased severity of RLS symptoms including potential extension of symptoms to new areas of the body that were not previously affected. In one study, augmentation occurred more frequently in patients with more severe pretreatment RLS symptoms and those on higher doses of carbidopa/levodopa (≥200/50 mg) (16). It was severe enough to warrant a change in medication in 50% of RLS patients. In the same study, 20% of RLS patients treated with levodopa experienced early morning rebound, when symptoms reappear at a time consistent with withdrawal effects of the medication. As a result of these problematic side effects, use of levodopa has fallen out of favor for daily, long-term treatment of RLS. However, levodopa may still be useful for intermittent use on an as-needed basis in patients with occasional RLS symptoms (5) or as an as-needed supplement when rapid relief of RLS symptoms is required.
Nonergot-derived Dopamine Agonists. Nonergot dopamine agonists, including ropinirole, pramipexole, and rotigotine, have become the mainstay for treatment of RLS because of their efficacy, as well as the reduced incidence of augmentation compared to levodopa. In addition, they are the only medications approved by the FDA for treatment of RLS. The nonergot dopamine agonists have been tested in a large number of randomized, placebo-controlled trials, which all used the IRLS as the primary outcome measure as opposed to levodopa trials.
TABLE 12.3 Pharmacologic Treatment of RLS and PLMD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ropinirole. Ropinirole has a fairly rapid onset of action, reaching peak plasma levels in 1.5 hours, and it has a half-life of 6 hours. Metabolized by the liver, it has some potential for drug interactions through the P450 1A2 pathway. It is administered at doses of between 0.25 mg to 4 mg. The FDA-approved dosing schedule calls for administration 1 to 3 hours before bedtime. In practice, ropinirole is sometimes dosed on an off-label schedule 1 to 3 hours before symptom onset and, in some cases, twice daily. The mean effective dose has often been between 1.5 and 2 mg/day in clinical trials (17,18).
Ropinirole resulted in a significant decrease in the IRLS score compared to placebo in several double-blind, placebo-controlled, randomized trials conducted over 4 to 12 weeks, and it was well tolerated by patients (17, 18, 19 and 20). In one study, ropinirole did not show a statistically significant improvement in IRLS score (21). However, there was a significant improvement in periodic limb movements during wake and sleep, as well as several sleep parameters, including sleep onset latency. Ropinirole resulted in a lower rate of relapse compared to placebo in one long-term study when patients were treated with ropinirole for 24 weeks, followed by an additional 12 weeks of ropinirole or placebo in a subset of subjects (22). IRLS scores also significantly improved. Ropinirole was well tolerated during the 36 weeks, although the trial was not specifically designed to evaluate augmentation. Overall, side effects of ropinirole have been mild in clinical trials, with common reactions including nausea, dizziness, somnolence, and headache (19,20). Ropinirole is an effective treatment option for RLS, and it appears to be well tolerated in both short- and long-term studies.
Pramipexole. Compared to ropinirole, pramipexole has a slower onset of action (1 to 3 hours) and a longer elimination half-life (10 hours). Pramipexole undergoes very little metabolism, and it is excreted almost entirely in the urine, mostly in the form of unaltered drug. Pramipexole is generally administered at doses between 0.25 mg and 1 mg, and, like ropinirole, it can be dosed on-label 1 to 3 hours before bedtime or off-label 1 to 3 hours before symptom onset.
There have been several randomized, double-blind, placebo-controlled trials lasting between 3 and 12 weeks, which have noted improvement in IRLS scores as well as the Clinical Global Impressions Improvement Scale (CGI) with pramipexole (23, 24 and 25). Other studies have noted improvements in periodic limb movements of sleep (23,26,27) and sleep parameters such as sleep-onset latency and total sleep time (27). Pramipexole was well tolerated during these studies.
There have been several trials that examined the effectiveness and tolerability of pramipexole over an extended period of time. One prospective, open-label study involved a 6-month initial period on pramipexole, followed by 6 months on pramipexole or placebo (28). More control subjects than RLS patients experienced worsening on the IRLS and CGI. Overall, pramipexole appeared to maintain its effectiveness without significant side effects. No augmentation was noted during this study. During a retrospective study with a mean follow-up of 27 months, pramipexole maintained effectiveness over time and side effects were generally mild. However, augmentation developed in 33% of patients (29). Another retrospective study found a similar rate with 32% of patients experiencing augmentation, as well as 46% developing tolerance (30). Overall, common side effects for pramipexole have been similar to ropinirole, including nausea, somnolence and dizziness. (31) Thus, pramipexole is an effective RLS treatment for short and long-term use, although rates of tolerance and augmentation vary.
Rotigotine. Rotigotine is a transdermal patch, with a recommended dose of between 1 and 3 mg/24 hours for RLS (32). The medication is delivered continuously through the skin, and it is dosed once daily. As with all dopamine agonists, rotigotine was
originally designed for treatment of Parkinson disease (PD), with the goal of avoiding the complications of intermittent dosing, avoiding interactions with food, and as an alternative in patients with swallowing difficulties (33). In RLS patients, providing a steady concentration of the drug has the theoretical potential to reduce augmentation and rebound. Rotigotine is metabolized by the liver, which involves several p 450 enzymes, and it is primarily excreted in the urine. The half-life is 5 to 7 hours.
originally designed for treatment of Parkinson disease (PD), with the goal of avoiding the complications of intermittent dosing, avoiding interactions with food, and as an alternative in patients with swallowing difficulties (33). In RLS patients, providing a steady concentration of the drug has the theoretical potential to reduce augmentation and rebound. Rotigotine is metabolized by the liver, which involves several p 450 enzymes, and it is primarily excreted in the urine. The half-life is 5 to 7 hours.
The rotigotine patch is a newer agent compared to ropinirole and pramipexole, and there have been fewer placebo-controlled trials using rotigotine. The first was a 1-week, double-blind, placebo-controlled pilot study, which found significant improvement in the IRLS and the CGI, but only at doses of 4.5 mg/24 hours (34). During a 6-week, double-blind, randomized, placebo-controlled trial, IRLS scores statistically improved at doses of 1 mg/24 hours to 4 mg/24 hours (35). A dose of 1 to 3 mg/24 hours was recommended as the maintenance dose because 4 mg/24 did not provide additional benefit. In a long-term randomized, double-blind, placebocontrolled study lasting 6 months, patients given 1 to 3 mg/24 hours of rotigotine experienced statistically significant improvement in the IRLS and the CGI compared to placebo (36). During this study, side effects of rotigotine were generally mild. However, skin reactions from the transdermal system were present in 43% of patients on rotigotine. Nausea occurred less frequently than for oral dopamine agonists. Rates of augmentation were no different from placebo during this trial. During a 1-year open label study, skin reactions continued to be common (40%) (37). Nausea and fatigue were also noted, but no augmentation was reported. At doses of 1 to 3 mg/24 hours, rotigotine is an alternative to oral nonergot dopamine agonists for short- and long-term use.
Safety and Tolerability. Overall, dopamine agonists have been well tolerated during short- and long-term clinical trials examining efficacy and safety in the treatment of RLS. The total daily dose of dopamine agonists used for treatment of RLS is significantly lower than that used for PD, often only about 10% of the dose used for PD. Additionally, it is administered once a day in the evening as opposed to three times a day. The most common side effects for this class of drugs have generally been mild and, as indicated above, have included nausea, somnolence/fatigue, and dizziness.
Patients taking dopamine agonists for PD have experienced additional side effects, including sleep attacks. Some PD patients have fallen asleep while driving. This symptom has not been noted in short- or long-term studies of dopamine agonists in RLS. One study attempted to specifically address this concern by administering a survey to a group of 24 RLS patients taking pramipexole, without any report of sleep attacks reported among the group surveyed (38). However, the number of patients in this study was small. The average daily dose for the patient’s taking dopamine agonists in this study was 0.37 mg, while the PD patients who had sleep attacks were taking an average dose of 2.9 mg a day (39). Other side effects described with use of dopamine agonists in PD include gambling and increased sexual desire. Recent evidence has suggested that RLS patients on dopamine agonists may be susceptible to such symptoms (40, 41 and 42)
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
