24 Restless Legs Syndrome

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1 24 Restless Legs Syndrome Mathew Clark, MD CONTENTS INTRODUCTION DESCRIPTION EPIDEMIOLOGY DIAGNOSIS TREATMENT MANAGEMENT OF RESTLESS LEGS SYNDROME SOURCES INTRODUCTION Restless legs syndrome (RLS) has been called the most common disorder that is never heard of. Although most primary care physicians have developed at least a passing familiarity with RLS in recent years, it remains true that this condition is very much underdiagnosed and undertreated. In an effort to promote more widespread awareness of RLS in the medical community and to share up-to-date knowledge regarding management of this condition, several guidelines, updates, and management algorithms have been published. These are summarized next. DESCRIPTION RLS has four essential diagnostic features: 1. An urge to move the legs, usually accompanied by uncomfortable sensations. 2. The urge to move or uncomfortable sensations that begin during periods of rest or inactivity. 3. These sensations are partially or totally but temporarily relieved by movement. 4. Symptoms are worse in the evening or at night. These symptoms may be infrequent, or they may be nearly constant, persisting throughout the day. Symptoms may be quite mild, and only noticeable in From: Current Clinical Practice: Essential Practice Guidelines in Primary Care Edited by: N. S. Skolnik Humana Press, Totowa, NJ 317

2 318 Clark certain situations, or they may be experienced as intense and nearly unbearable. Affected patients typically have trouble with sedentary activities, such as sitting through meetings, being a passenger on a long trip, or going to the theater. Insomnia is often a significant problem when the combination of inactivity and time of day may make initiation of sleep very difficult. Although RLS is by definition a condition that is experienced only during wakefulness, many patients with RLS also experience a related phenomenon, periodic leg movements of sleep (PLMS). PLMS condition causes stereotypical contractions of the legs as the patient sleeps. These contractions are often of sufficient intensity and frequency to significantly disrupt sleep. Accordingly, patients with RLS and PLMS often have trouble with both the initiation and maintenance of sleep, leading to significant daytime sleepiness and fatigue (1 3). EPIDEMIOLOGY In the United States, between 5 and 10% of the adult population experiences symptoms of RLS. Not all of these individuals will experience symptoms of sufficient frequency or intensity to warrant treatment. Symptoms tend to become more common with advancing age, and are more common in elderly patients than in young adults. There is a family history of RLS in two-thirds of affected patients. Most cases of RLS are idiopathic; the cause of these symptoms is currently not well understood. There are some conditions in which RLS is seen with greater frequency. Iron deficiency even at levels insufficient to cause anemia is associated with more frequent symptoms of RLS. Pregnancy is associated with RLS, with 19% of pregnant women reporting some symptoms; about one-third of these women describe their symptoms as severe. Patients with renal failure often experience RLS; studies have reported a prevalence of 20 57% in this population. DIAGNOSIS Diagnosis of RLS is by history. Patients should experience all four of the listed diagnostic criteria: the urge to move accompanied by dysesthesias, symptoms brought on at rest, relieved by movement, and worse in the evening or night. There is no role for a polysomnogram in diagnosing RLS, although this may be helpful in diagnosing PLMS. Iron status should be assessed. A serum ferritin is the recommended test; levels less than 50 are associated with a greater prevalence of RLS symptoms, even in the absence of anemia. TREATMENT Nonpharmacological Not all patients with RLS require treatment with medications. Recommended nonpharmacological measures include the following:

3 Chapter 24 / Restless Legs Syndrome 319 Replacement of iron, if iron deficiency is documented. Mental alerting activities, such as video games or crossword puzzles, at times of boredom/physical inactivity. Trial of abstinence from alcohol, nicotine, and caffeine. Trial of avoidance of medications with potential to worsen RLS symptoms. These medications include antidepressants (except buproprion), neuroleptic agents, dopamine-blocking antiemetics (such as metoclopramide), and sedating antihistamines. Medications The following classes of medications have demonstrated efficacy in treating RLS symptoms: Dopaminergic medications: Medications in this class include levodopa/carbidopa combinations (Sinemet) and the dopamine agonists (DA) such as pergolide (Permax), ropinirole (Requip), and pramipexole (Mirapex). Balancing their excellent track record in relieving RLS symptoms is a tendency to develop unacceptable side effects. These include augmentation (the development of RLS symptoms earlier in the day after a bedtime dose of medication) and rebound (a wearing off of medication with an increased intensity of symptoms). Approximately 70% of patients taking regular levodopa/carbidopa will develop augmentation or rebound. This statistic is considerably smaller for those using DA. Opioids: Even weak opioids such as codeine or propoxyphene may be helpful in RLS, as may the opioid agonist tramadol. Higher potency opioids such as hydrocodone, oxycodone, or methadone are often helpful in more severe cases when weaker opioids are ineffective. Concerns about side effects and dependence make this a second-line option in most algorithms, yet this class of medications has been shown to maintain efficacy over long periods without a need for dose escalation. Anticonvulsants: These includes both carbamazepine and gabapentin, which are effective in treating RLS. Use of these agents may be limited by concerns about cost and side effects. They may be particularly helpful in situations involving neuropathy or a painful quality to the RLS symptoms. Benzodiazepines: These agents have demonstrated efficacy in RLS, particularly in patients for whom sleep-onset insomnia is a primary concern. Use of these medications is limited by concerns about dependence, tolerance, and daytime drowsiness. Clonidine and magnesium: These medications have demonstrated efficacy in small trials. No specific recommendation is currently made regarding their use. MANAGEMENT OF RESTLESS LEGS SYNDROME For purposes of management, the algorithm of the Medical Advisory Board of the RLS Foundation divides RLS into intermittent, daily, and refractory types.

4 320 Clark Intermittent RLS Patients with intermittent RLS have symptoms that are troublesome enough, when present, to require treatment, but that do not occur frequently enough to necessitate daily treatment. Recommendations, in addition to nonpharmacological measures, include the intermittent use of the following medications: Carbidopa/levodopa, 25/100 (0.5 1 tablet) or controlled-release (CR) 25/100 (1 tablet) can be used at bedtime or for RLS associated with specific activities, such as airplane or lengthy car rides. DA. The nonergot DAs (ropinirole or pramipexole) appear to have fewer troublesome side effects. Because these medications take min to begin working, they are of limited usefulness once symptoms have begun. Low-potency opioids or opioid agonists, such as propoxyphene ( mg), codeine (30 60 mg), or tramadol ( mg). Benzodiazepines or benzodiazepine agonists (temazepam, triazolam, zolpidem, and zaleplon). Daily RLS Patients in this category have RLS that is frequent and troublesome enough to require daily therapy. Recommendations, in addition to nonpharmacological measures, include use of the following medications: DA are the drugs of choice in most patients with daily RLS. Pramipexole (Mirapex) is normally given as mg once daily, taken 2 h before major RLS symptoms usually start. This dose may be increased by mg for every 2 3 d until symptoms are relieved. Most patients need 0.5 mg or less; doses up to 2 mg may be needed. Ropinirole (Requip) is dosed at 0.25 mg daily, also 2 h before symptoms, and increased by 0.25 mg for every 2 3 d as needed. Most patients require 2 mg or less; doses up to 4 mg may be needed. Gabapentin may be an alternative choice, particularly when symptoms are painful as described earlier. The treatment is usually once or twice daily, given late in the afternoon or before sleep. Dosing may start at mg per dose; mean daily doses of mg were used in one trial. Low-potency opioids (e.g., codeine or propoxyphene) or tramadol may be an alternative choice. Refractory RLS Patients with refractory RLS symptoms have daily RLS treated with a DA with one or more of the following: inadequate initial response despite adequate doses, response that has become inadequate with time, intolerable adverse effects, augmentation that is not controllable with additional earlier doses of the drug. In addition to the following approaches, referral to a RLS specialist should be considered:

5 Chapter 24 / Restless Legs Syndrome 321 Change to gabapentin. Change to a different DA. Add gabapentin, a benzodiazepine, or an opioid. Change to a high-potency opioid (oxycodone 5 15 mg), hydrocodone (5 15 mg), methadone (5 10 mg), or tramadol ( mg). No specific recommendations address the treatment of RLS in pregnant women or children. SOURCES 1. Hening W, Allen R, Earley C, Kushida C, Picchietti D, Silber M (1999) The treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine Review. Sleep 22: Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MH (2004) Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 27: Silber MH, Ehrenberg BL, Allen RP, et al. (2004) Medical Advisory Boards of the Restless Legs Syndrome Foundation. An algorithm for the management of restless legs syndrome. Mayo Clin Proc 79(7):