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Restless Legs Syndrome Learning Objectives Upon successful completion of this course, you will be able to: ● Define the term “restless legs syndrome” (RLS) ● Identify the causes of this syndrome ● List the signs and symptoms of RLS ● Identify the available treatments and medications related to this syndrome News Item from the New York Times July 19, 2007 Scientists Find Genetic Link for a Disorder (Next, Respect?) By NICHOLAS WADE Imagine you keep waking up with a fierce urge to move your legs, each time further eroding your sleep quota and your partner’s patience. You have restless legs syndrome, a quaintly named disorder whose sufferers may get more respect now that its genetic basis has been identified. Two independent teams, one in Germany and one in Iceland, have identified three variant sites on the human genome which predispose people to the condition. The advance should help scientists understand the biological basis of the disorder, which could lead to new ideas for treatment. The new findings may also make restless legs syndrome easier to define, resolving disputes about how prevalent it really is. The disorder is a “case study of how the media helps make people sick,” two researchers at Dartmouth Medical School, Steven Woloshin and Lisa Schwartz, wrote recently in the journal PLoS Medicine. They argued that its prevalence had been exaggerated by pharmaceutical companies and uncritical newspaper articles, and that giving people diagnoses and powerful drugs were serious downsides of defining the elusive syndrome too broadly. Discovery of the genetic basis of the disorder “puts restless legs syndrome on a firmer footing,” said Dr. Christopher Earley, a physician at Johns Hopkins University who treats the malady. Dr. Woloshin said that he “wouldn’t change a thing” in his article. He fears the new reports “will be used to validate restless legs syndrome as a highly prevalent disease,” he said. The two groups of researchers have both used the latest method in trawling the human genome for disease genes. Called Whole Genome Association, the method depends on the use of powerful chips to detect up to 500,000 genetic variants at a time. By comparing patients’ genomes with those of unaffected people, researchers can pinpoint the variants associated with the disease. One research team, led by Juliane Winkelmann and Thomas Meitinger at the Institute of Human Genetics in Munich, reports in Nature Genetics today that it has found variants in three genes that 1 Copyright@2002 confer risk for restless syndrome. They detected the variants in a German patient population and confirmed the findings in French-Canadians. Independently, a team led by Hreinn Stefansson of Decode Genetics in Reykjavik, Iceland, says today in The New England Journal of Medicine that it has found one of the same genetic variants associated with restless legs syndrome in Icelanders and in Americans recruited at Emory University in Atlanta. Dr. Winkelmann said the three genes implicated in her study had come as a complete surprise because they had never been suspected of involvement in the syndrome. “Now we have for the first time the prerequisite to study the biological basis of restless legs syndrome,” she said. Kari Stefansson, chief executive of Decode Genetics, said his company had linked variations in the gene known as BTBD9 with periodic leg movements during sleep and with low iron levels in the blood, two clinical features already associated with the syndrome. He said Decode had missed, but subsequently confirmed, the two other genes identified in Dr. Winkelmann’s study. Experts find it hard to assess how common restless legs syndrome is because it covers a broad spectrum of symptoms, the milder forms of which are harmless, and is also mimicked by several other diseases, like nocturnal cramps. Dr. Stefansson said he believed restless legs syndrome occurred in 5 percent to 15 percent of European populations. Dr. Woloshin said the “most credible” estimate is 3 percent. Still, even that proportion could mean that a lot of spouses are getting kicked out of bed every night. The variant form of BTBD9 is very common but in most people causes no symptoms. But it accounts for 50 percent of cases of restless leg syndrome in European populations, Decode Genetics calculates. The prevalence of the disease varies widely between ethnic groups, being found in only 0.1 percent of Singaporeans and 2 percent of Ecuadoreans. Many human genes were first described by geneticists who identified counterpart genes in the laboratory fruitfly. Fruitfly researchers consider it a matter of pride to give genes colorful names, but these are often moderated or disguised by medical researchers who feel absurd names will not help attract research funds. BTBD9, the gene in today’s two studies, stands for broad complex-tramtrackbric-a-brac-domain 9. Introduction What Is Restless Legs Syndrome? Restless legs syndrome (RLS) is a sensory disorder causing an almost irresistible urge to move the legs. The urge to move is usually due to unpleasant feelings in the legs that occur when at rest. People with RLS use words such as creeping, crawling, tingling, or burning to describe these feelings. Moving the legs eases the feelings, but only for a while. The unpleasant feelings may also occur in the arms. Effects of RLS RLS can make it hard to fall asleep and stay asleep. People with RLS often don’t get enough sleep and may feel tired and sleepy during the day. This can make it difficult to: Concentrate, making it harder to learn and remember things 2 Copyright@2002 Work Carry out other usual daily activities Take part in family and social activities Not getting enough sleep can also make you feel depressed or have mood swings. RLS can range from mild to severe, based on: How much discomfort there is in the legs and arms Whether there is the need to move around How much relief there is from moving around How much sleep disturbance there is How tired or sleepy the person is during the day How often the symptoms occur How severe the symptoms are on most days How well the person is able to carry out daily activities How angry, depressed, sad, anxious, or irritable the person feels Types of RLS There are two types of RLS: Primary RLS is the most common type of RLS. It is also called idiopathic RLS. “Primary” means the cause is not known. Primary RLS, once it starts, usually becomes a lifelong condition. Over time, symptoms tend to get worse and occur more often, especially if they began in childhood or early in adult life. In milder cases, there may be long periods of time with no symptoms, or symptoms may last only for a limited time. Secondary RLS is RLS that is caused by another disease or condition or, sometimes, from taking certain medicines. Symptoms usually go away when the disease or condition improves, or if the medicine is stopped. Periodic Limb Movement Disorder Most people with RLS also have a condition called periodic limb movement disorder (PLMD). PLMD is a condition in which a person’s legs twitch or jerk uncontrollably about every 10 to 60 seconds. This usually happens during sleep. These movements cause repeated awakenings that disturb or reduce sleep. PLMD usually affects the legs but can also affect the arms. 3 Copyright@2002 Outlook RLS can be unpleasant and uncomfortable. However, there are some simple self-care approaches and lifestyle changes that can help in mild cases. RLS symptoms often improve with medical treatment. Research is ongoing to better understand the causes of RLS and to develop better treatments. What Causes Restless Legs Syndrome? Primary RLS In most cases of restless legs syndrome (RLS), no cause can be found. When no cause can be found, the condition is called primary RLS. It is known, however, that primary RLS tends to run in families. People whose parents have RLS are more likely to develop the disorder. This suggests that there may be a genetic link that increases the chance of getting RLS. Secondary RLS Secondary RLS is RLS that is caused by another disease or condition, or as a side effect of certain medications. Some of the diseases and conditions that can cause RLS are: Iron deficiency (with or without anemia) Kidney failure Diabetes Parkinson’s disease Damage to the nerves in the hands or feet (peripheral neuropathy) (pe-RIF-e-ral noo-ROP-athe) Rheumatoid arthritis (ROO-ma-toyd ar-THRI-tis) Pregnancy RLS is common in pregnant women. It usually occurs during the last 3 months of pregnancy and usually improves or disappears within a few weeks after delivery. However, some women may continue to have symptoms after giving birth or may develop RLS again later in life. Some of the types of medicines that can cause RLS are: Antiseizure medicines Antinausea medicines Antidepressants Some cold and allergy medicines RLS symptoms usually go away when the medicine is stopped. 4 Copyright@2002 Certain substances can trigger RLS symptoms or make them worse. These substances include: Caffeine Alcohol Tobacco Who Is At Risk for Restless Legs Syndrome? Restless legs syndrome (RLS) may affect as many as 12 million people in the United States. Gender RLS affects both men and women. The disorder occurs more often in women than in men. Age The number of cases of RLS rises with age. Many people with RLS are diagnosed in middle age. But in up to two out of every five cases, the symptoms of RLS begin before age 20. People who develop RLS early in life usually have a family history of the disorder. Race/Ethnic Group RLS can affect people of any race or ethnic group. The disorder is more common in persons of northern European descent. Pregnancy RLS is common in pregnant women. It usually occurs during the last 3 months of pregnancy and usually improves or disappears within a few weeks after delivery. What Are the Signs and Symptoms of Restless Legs Syndrome? Restless legs syndrome (RLS) has several major signs and symptoms: An almost irresistible urge to move the legs or arms when sitting or lying down An unpleasant feeling in the legs Difficulty falling asleep or staying asleep because of the unpleasant feelings in the legs or arms Daytime sleepiness, which results from a lack of restful sleep due to the repeated limb movements Urge To Move RLS gets its name from the urge to move the legs when sitting or lying down. This urge is due to unpleasant feelings in the legs that are relieved by movement. Typical movements are: Pacing and walking 5 Copyright@2002 Jiggling the legs Stretching and flexing Tossing and turning Rubbing the legs Unpleasant Feelings The urge to move the legs usually is due to unpleasant feelings in the legs. People with RLS describe these feelings as: Creeping Crawling Pulling Itching Tingling Burning Aching Painful Hard to describe Children may describe RLS symptoms differently than adults. The unpleasant feelings in RLS usually occur in the lower leg (calf). But the feelings can occur at any place between the thigh and the ankle and also in the arm. The feelings are worse: When lying down or sitting for a long period of time During the evening or night, more so than during the day The unpleasant feelings also: Make it hard to fall asleep or stay asleep Are not as bad or go away when you move Duration and Severity 6 Copyright@2002 RLS symptoms tend to get worse over time. They may begin in childhood and develop slowly over several years. People with early symptoms are more likely to have other family members with RLS than people who develop RLS later in life. Symptoms tend to worsen faster when RLS occurs later in life. RLS that occurs later in life is also more likely to result from an underlying condition or illness than RLS that occurs early in life. People with mild symptoms may only notice them when they are still or awake for a long time, such as on a long airplane trip. How Is Restless Legs Syndrome Diagnosed? The way that you describe your symptoms is very important in diagnosing restless legs syndrome (RLS). Your doctor will: Take a complete medical history Do a complete physical examination Order other tests The diagnosis of RLS usually requires the following four conditions be present: 1. An urge to move the legs due to an unpleasant feeling in the legs. 2. The urge to move the legs, or the unpleasant feelings in the legs, begins or gets worse when you are at rest or not moving around frequently. 3. The urge to move the legs, or the unpleasant feelings in the legs, is partly or completely relieved by movement (such as walking or stretching) for as long as the movement continues. 4. The urge to move the legs, or the unpleasant feelings in the legs, is worse in the evening and at night, or only occurs in the evening or at night. Medical History The caregiver will take a medical history and ask questions such as: Can you describe your symptoms? When did your symptoms first begin? When during the day or night do the symptoms usually occur? When are your symptoms worse? Do symptoms interfere with your sleep? 7 Copyright@2002 The caregiver will also ask about your sleep habits, such as: The time you go to bed and get up Your routine before going to bed Noise, light, and interruptions in the room where you sleep Whether you snore The caregiver will ask about how you feel during the day, including whether: You are tired and sleepy when you wake up and during the day. You have trouble concentrating. You doze off or have difficulty staying awake doing routine tasks, especially driving. The caregiver will ask questions to find out if your symptoms are a result of a possible underlying condition. Questions might include: Do members of your family have similar symptoms? What medicines (over-the-counter and prescription) do you take? Do you snore loudly and frequently? Do you gasp for air during sleep? Do you use caffeine, tobacco, or alcohol? Physical Exam A physical exam is done to: Identify any underlying condition that may cause RLS Rule out other disorders The caregiver also will pay special attention to: The nerves in your spinal cord (especially) and legs and arms The blood flow in your legs and arms Other Tests There is no test currently available to diagnose RLS. 8 Copyright@2002 However, blood tests can be used to look for underlying conditions that can cause RLS. These tests check for: Low iron stores or iron deficiency Diabetes Kidney disease Other vitamin and mineral deficiencies How Is Restless Legs Syndrome Treated? The goals of treatment for restless legs syndrome (RLS) are to: Relieve symptoms Increase the amount and quality of sleep Treat or correct any underlying condition that may cause RLS Types of treatment include: Lifestyle changes and other nondrug treatments Medicines Lifestyle Changes and Other Nondrug Treatments Lifestyle changes can improve and relieve symptoms of RLS. Lifestyle changes may be the only treatment needed for mild RLS. Some lifestyle changes that may help include: Avoid things that can make symptoms of RLS worse: o Tobacco o Alcohol o Caffeine—Chocolate, coffee, tea, and some soft drinks contain caffeine. Although it may seem to help overcome daytime sleepiness, caffeine usually only delays or masks RLS symptoms, and often makes them worse. o Some medicines—Some types of over-the-counter and prescription medicines can also make RLS symptoms worse. These include: Antidepressants (most of them) Antinausea medicines 9 Copyright@2002 Antipsychotic medicines Antihistamines Adopt good sleep habits: o Keep the bedroom or sleep area cool, quiet, comfortable, and free of unnecessary light. o Use the bedroom for sleeping, not for watching TV or using computers or cell phones. o Go to bed every night at the same time and wake up at the same time every morning. Some people with RLS find it helpful to go to bed later in the evening and get up later in the morning. The important thing is to get enough sleep so that you feel rested when you wake up. Follow a program of moderate exercise Other activities that also may help relieve symptoms include: Walking or stretching Taking a hot or cold bath Massaging the leg or arm Using heat or ice packs Medicines Medicines can help relieve some symptoms of RLS. Doctors prescribe medicines to treat RLS in people: With clearly defined symptoms Whose symptoms cannot be controlled by lifestyle and nondrug treatments No single medicine is helpful in all persons with RLS. It may take several changes in medicines and dosages to find the best approach. Sometimes, a medicine will work for a while and then stop working. Some medicines may not be safe for pregnant women. Always talk with your doctor before taking any medicines, even over-the-counter medicines. Specific medicines Medicines used to treat Parkinson’s disease also are used to treat RLS. Even though these medicines help reduce RLS symptoms, RLS is not a form of Parkinson’s disease. The medicines help reduce the amount of motion in the legs. They include: Levodopa (le-vo-DO-pa) 10 Copyright@2002 o Is best used to treat mild cases of RLS o Is short-acting o Works for a while but does not work long term in most people Dopamine agonists (pergolide (PER-go-lid), pramipexole (prah-mih-PEX-ohl), and ropinirole (roh-PIN-ih-roll)) o Are used to treat moderate and severe cases of RLS o Are used to treat mild cases of RLS if levodopa stops working o Are long-acting The U.S. Food and Drug Administration recently approved ropinirole to treat moderate to severe RLS. Other medicines may be used to treat RLS, including: Strong pain-relieving medicines (narcotics). o Used most often when symptoms are severe o May be used in people who don’t respond to dopamine agonists Sedatives (benzodiazepines (BEN-so-di-AZ-e-pens)). o Help with falling asleep o May cause daytime sleepiness o Are not recommended for people with sleep apnea and for older persons Medicines used to treat epilepsy (anticonvulsants: gabapentin (gab-ah-PEN-tin), carbamazepine (kar-bam-AZ-e-pen), and valproate (val-PROH-ate)). These types of medicines are: o Considered when dopamine agonists fail o Most effective in persons with daytime and evening symptoms, as well as sleep-onset symptoms, and in those who describe the unpleasant feelings in the legs as painful. Iron supplements, if iron deficiency appears to be contributing to RLS. Iron supplements should only be used if recommended by a doctor. Living With Restless Legs Syndrome 11 Copyright@2002 Restless legs syndrome (RLS) is often a lifelong condition. The symptoms may come and go frequently or disappear completely for long periods of time. They may get worse over time. Lifestyle changes and medicines can help control and relieve the symptoms of RLS. For severe symptoms, ongoing medicines may be needed. Persons affected should talk to their doctor about lifestyle changes and medicines that might help your symptoms. New treatments are being developed as research continues. RLS that occurs during pregnancy usually improves or disappears within a few weeks after delivery. Background The term restless legs syndrome (RLS) was used initially in the mid-1940s by Swedish neurologist Karl A. Ekbom to describe a disorder characterized by sensory symptoms and motor disturbances of the limbs, mainly during rest. However, early descriptions date back to the 17th century. It is recognized now as a neurologic movement disorder of the limbs, often associated with a sleep complaint. Patients with RLS have a characteristic difficulty in trying to depict their symptoms; they may report sensations such as an almost irresistible urge to move the legs, which are not painful but are distinctly bothersome; this can lead to significant physical and emotional disability. The sensations usually are worse during inactivity and often interfere with sleep, leading to walking discomfort, chronic sleep deprivation, and stress. Once correctly diagnosed, RLS can usually be treated effectively by relieving symptoms; in some secondary cases, it can even be cured. Pathophysiology: Pathogenesis of RLS is unclear. Ekbom originally proposed that it was mainly the result of accumulation of metabolites in the legs because of venous congestion. Peripheral nerve abnormalities also have been proposed, but no associated structural changes in nerve endings have been identified. RLS also has been linked to dopaminergic or opiate abnormalities. Centrally acting dopamine receptor antagonists reactivate symptoms when given to patients with the syndrome. Results of single-photon emission computed tomography (SPECT) have suggested deficiency of dopamine D2 receptors. Sympathetic hyperactivity also has been implicated on the basis of observations that sympathetic nerve blockade relieves periodic limb movements of sleep and that alpha-adrenergic blockers improve symptoms of RLS. Studies also have suggested possible underactivity of the serotonin and gammaaminobutyric acid (GABA) neurotransmitter systems. Frequency: In the US: RLS affects about 10-15% of the general population, with men and women affected equally. It is often unrecognized or misdiagnosed. Many patients are not diagnosed until 10-20 years after symptom onset. It may begin at any age, even as early as infancy, but most patients who are affected severely are middle-aged or older. Symptoms progress over time in about two thirds of patients and may be severe enough to be disabling. 12 Copyright@2002 Internationally: Although the exact prevalence is uncertain, limited studies have indicated that 2-15% of the population may experience symptoms of RLS. Mortality/Morbidity: The severity of symptoms in patients with RLS ranges from mild to intolerable. Although patients experience the sensations in their legs, they also may occur in the arms or elsewhere. RLS symptoms are generally worse in the evening and night and less severe in the morning. While RLS may present early in adult life with mild symptoms, usually by age 50 it progresses to daily severe disruption of sleep leading to decreased daytime alertness. RLS is associated with reduced quality of life in cross-sectional analysis. Sex: Although males and females are generally believed to be affected equally, a 2004 study by Berger et al showed that RLS affects women more frequently than men. In this specific study, parity was shown to be a major factor in explaining the sex difference and may guide further clarification of the etiology of the disease. Age: Although the prevalence of RLS increases with age, it has a variable age of onset and can occur in children. In patients with severe RLS, 33-40% had their first symptom before the age of 20 years, although the precise diagnosis of RLS was made much later. It usually progresses slowly to daily, severe disruption of sleep, typically after age 50. A childhood-onset restless legs syndrome has also been described. A study published in Dec 2004 by Kotagal and Silber concluded that iron deficiency and a strong family history were characteristic of this childhood-onset presentation. History: Diagnosis of RLS is based primarily on the clinical history. Often, patients do not bring RLS symptoms to the attention of the physician; therefore, including a few general sleep questions in the review of systems can be helpful. RLS patients typically report dysesthetic sensations described as "pins and needles," an "internal itch," or "a “creeping” or “crawling” sensation. The criteria for diagnosis of RLS are based on those developed by the International Legs Syndrome Study Group in 1995; 4 basic elements must be present to make the diagnosis. They are as follows: o A compelling urge to move the limbs, usually associated with paresthesias/dysesthesias o Motor restlessness, as seen in activities such as floor pacing, tossing and turning in bed, and rubbing the legs o Symptoms worse or exclusively present at rest (i.e., lying, sitting) with variable and temporary relief on activity o Circadian variation of symptoms, which are present in the evening and at night. Often, symptoms are relieved after 5:00 am. In more severe cases, symptoms can be present throughout the day without circadian variation. Other features commonly associated with RLS but not required for diagnosis include sleep disturbances and daytime fatigue; normal neurologic exam in primary RLS; and involuntary, repetitive, periodic, jerking limb movements, either in sleep or while awake and at rest. 13 Copyright@2002 Approximately 85% of patients with RLS have periodic leg movements of sleep (PLMS), usually involving the legs. PLMS is characterized by involuntary forceful dorsiflexion of the foot lasting 0.5-5 seconds and occurring every 20-40 seconds throughout sleep. A large majority of patients (85%) with RLS report difficulty falling asleep at night because of RLS, and they may experience excessive daytime somnolence because of poor sleep quality due to multiple PLMS-induced arousals. Physical: The physical examination is usually normal in patients with RLS; it is performed to identify secondary causes and to exclude other disorders. Causes: RLS can be primary or secondary. Primary RLS o In most cases, RLS is an idiopathic CNS disorder. Such idiopathic disease can be familial in 25-75% of cases. In the familial cases, it appears to follow a pattern of autosomal dominant inheritance. o Progressive decrease in age at onset with subsequent generations (i.e., genetic anticipation) has been described in some families. Patients with familial RLS tend to have an earlier age at onset (< 45) and slower progression. o Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS. Secondary RLS o RLS can develop as a result of certain conditions or factors, particularly iron deficiency and peripheral neuropathy. These 2 conditions should be excluded before RLS is labeled as primary. Because of the prevalence of these conditions in the general population, their association with RLS needs to be interpreted with caution. D Other Problems to be Considered: Nocturnal leg cramps: These are typically unilateral, painful, palpable, involuntary muscle contractions, often local, with a sudden onset. Like RLS, they may have a circadian pattern and often occur at rest. However, the leg cramps have physical changes including a muscle hardening not seen in RLS. Akathisia: It is characterized by excessive urge to move the entire body, without a focal sensory complaint in the limbs; often it does not correlate with rest or show circadian variation, and it usually results from medications such as neuroleptics or other dopamine-blocking agents. It also may be caused by selective serotonin reuptake inhibitors (SSRIs). Peripheral neuropathy: It can cause leg symptoms that are different from those of RLS; symptoms usually are neither associated with motor restlessness nor helped by movement and do not worsen in evening or nighttime. Typically, sensory complaints are numbness, tingling, or 14 Copyright@2002 pain. Small-fiber sensory neuropathies, as seen in diabetes, often are confused with RLS; patients with neuropathies may have both neuropathic symptoms and symptoms of RLS. Vascular disease (e.g., deep vein thrombosis) Painful legs moving toes: Unlike RLS, this condition is not associated with a focal urge to move the limbs, and it does not show a clear circadian pattern. RLS must be distinguished from sleep-related leg conditions, such as nocturnal leg cramps. These periodic limb movements, also known as PLMS or nocturnal myoclonus, which may be associated with RLS, are stereotyped, repetitive flexion of the limbs (legs alone or legs more than arms), lasting 0.5-5 seconds and usually occurring every 20-40 seconds. IFFERENTIALS Lab Studies: If a secondary cause is suspected on the basis of history, abnormal findings on neurologic examination, or poor response to treatment, a laboratory evaluation should be done. Tests include measurement of levels of BUN, creatinine, fasting blood glucose, ferritin, magnesium, thyroid-stimulating hormone (TSH), vitamin B-12, and folate; Venereal Disease Research Laboratory (VDRL) test; glucose tolerance test; and CBC count. In a recent controlled study, Tuisku et al demonstrated that the general lower limb activity measured by 3-channel actometry is a promising objective measure of RLS severity. The same authors further evaluated the method in measuring RLS symptom severity in an open, single-day pramipexole intervention with 15 patients with RLS. They reported that both their standardized actometric parameters (nocturnal lower limb activity and controlled rest activity) decreased significantly during the intervention in parallel with the subjectively reported relief of RLS symptoms. Other Tests: Needle electromyography and nerve conduction studies should be considered if polyneuropathy is suspected on clinical grounds, even if results of neurologic examination are apparently normal. Polysomnography may be necessary to quantify PLMS or to characterize sleep architecture, especially in patients who continue to have significant sleep disturbances despite relief of RLS symptoms with treatment. Because RLS is primarily a subjective disorder, a subjective scale has been proposed as the optimal instrument to meet this need. In March 2003, a study was published after 20 centers from 6 countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). This scale, the IRLSSG rating scale, was administered to 196 RLS patients, most of whom were taking some medication, and 209 control subjects. The results of this study showed that the IRLSSG scale had high levels of internal consistency, interexaminer reliability, test-retest reliability over a 2-4 week period, and convergent validity. This scale is an interesting tool and should be considered for its value as a brief, 15 Copyright@2002 patient-completed instrument that can be used to assess RLS severity for clinical assessment, research, or therapeutic trials. Medical Care: Therapeutic success is obtained when the physician tailors the treatment on the basis of the patient's specific symptoms and whether the symptoms are bothersome. Therapy should not be withheld if RLS is impairing the patient's quality of life. Nonpharmacologic management o Patients with mild RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Offending medications also should be discontinued. Mild exercise is helpful in some patients. In general, physical measures are only partially or temporarily helpful. Behavioral treatments with circadian adjustments permit later sleep times. o Some patients benefit from different physical modalities, such as hot or cold baths, whirlpool baths, limb massage, or vibratory or electrical stimulation of the feet and toes before bedtime. o Supplementation to correct vitamin deficiencies, electrolytes, or iron may improve symptoms in some patients. In iron deficiency, for example, ferrous sulfate 325 mg may be given with 250 mg of vitamin C. Absorption is increased by taking this on an empty stomach and waiting 60 minutes before eating. o Patients with prominent varicose veins in the legs may benefit from Ted hose. o Those with uremia or anemia may find relief after kidney transplantation or correction of anemia, respectively. Diet: Patients with RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Drug therapy for primary RLS is largely symptomatic, since cure is possible only in secondary disease. In some patients, RLS symptoms occur sporadically with spontaneous remissions lasting weeks or months. Use of pharmacologic treatment on an irregular basis is warranted in such cases. Continuous pharmacologic treatment should be considered if patients complain of RLS symptoms at least 3 nights each week. Drug Category: Dopaminergic agents -- These agents may improve sensory symptoms associated with RLS. Agents like pramipexole, ropinirole, and bromocriptine are less likely than the combination drug levodopa/carbidopa to produce augmentation or rebound and can be used alone or along with levodopa in patients in whom one of these conditions develops. Adverse effects of dopamine agonists include nausea, light-headedness, drowsiness, and postural hypotension. Drug Name Levodopa with carbidopa (Sinemet) -- Can improve sensory symptoms and PLMS in primary RLS and in secondary RLS due to uremia. Most patients experience benefits with doses of 25/100 16 Copyright@2002 (in mild cases), with maximum dose of 50/200 mg/d. Doses >50/200 mg accompanied by marked augmentation of symptoms in 85% of patients. Augmentation defined as earlier onset during evening or after assuming restful position; as increased intensity in morning; or as extension of symptoms to upper part of body. Adjunctive therapy with reduction of levodopa dose or discontinuation of levodopa and substitution with dopamine agonist drug may help. Adult Dose Pediatric Dose Contraindications 25/100-50/200 mg PO qd Not established Documented hypersensitivity; narrow-angle glaucoma; MAOI use within last 14 d; melanoma Interactions Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects of levodopa; levodopa toxicity increases with antacids and MAOIs Pregnancy C - Safety for use during pregnancy has not been established. Precautions Certain adverse CNS effects (e.g., dyskinesias) may occur at lower dosages and earlier in therapy with sustained release form; caution in patients with history of MI, arrhythmias, asthma, or peptic ulcer disease; sudden discontinuation of levodopa may cause worsening of Parkinson disease; high-protein diets should be distributed throughout day to avoid fluctuations in levodopa absorption Drug Name Pergolide mesylate (Permax) -- Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market. Potent, long-acting dopamine D1 and D2 receptor agonist that has been shown to be effective in RLS, even in patients who are unresponsive to levodopa. 17 Copyright@2002 Adult Dose Pediatric Dose Contraindications 0.1-0.5 mg/d PO am and hs Not established Documented hypersensitivity Interactions Dopamine antagonists such as neuroleptics, phenothiazines, butyrophenones, thioxanthines, or metoclopramide may diminish effectiveness; because drug is more than 90% bound to plasma proteins, exercise caution if coadministered with other drugs known to affect protein binding Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions May cause valvular heart disease (yearly echocardiograms recommended for patients on chronic therapy); inhibits secretion of prolactin; causes transient rise in serum concentrations of growth hormone and decrease in serum concentrations of luteinizing hormone; adverse effects include nausea, hypotension, hallucinations, and somnolence; use caution in patients who have been treated for cardiac dysrhythmias; may cause or exacerbate preexisting states of confusion and hallucinations or dyskinesia Drug Name Bromocriptine mesylate (Parlodel) -- Dopamine D2 receptor agonist that has been found to be effective in RLS. However, usually poorly tolerated because of nausea and orthostatic hypotension. Other dopamine agonists such as pergolide or pramipexole preferred. Adult Dose 7.5 mg PO qd am and hs Pediatric Dose Not established Contraindications Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders Interactions Ergot alkaloids may increase toxicity; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, reserpine may decrease effects Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution in renal or hepatic disease Drug Name Pramipexole (Mirapex) -- D2 and D3 receptor 18 Copyright@2002 agonist recently approved by FDA for treating Parkinson disease; also used effectively in patients with RLS. Adult Dose Pediatric Dose Contraindications 0.125-1.0 mg PO pm or hs Not established Documented hypersensitivity Interactions Cimetidine may increase toxicity; increases levodopa levels Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution in renal insufficiency and pre-existing dyskinesias; cases of rhabdomyolysis have been reported in patients with advanced Parkinson disease treated with pramipexole Drug Name Ropinirole hydrochloride (Requip) -- Dopamine D2 receptor agonist recently approved by FDA for treating Parkinson disease; also has been used in patients with RLS. It is a nonergoline, nonphenolic indolone derivative. 0.5-5.0 mg PO am or hs Adult Dose For treatment of moderate-to-severe primary RLS, a dose titration recommended; doses should be titrated, when appropriate, based upon clinical response and tolerability; all doses are once daily 1-3 h before bedtime (product information Requip, ropinirole hydrochloride tablets, 2005): 0.25 mg for days 1 and 2 0.5 mg for days 3-7 1 mg for wk 2 1.5 mg for wk 3 2 mg for wk 4 2.5 mg for wk 5 3 mg for wk 6 4 mg for wk 7 Doses >4 mg qd have not been adequately studied in patients with RLS; ropinirole has been discontinued without a taper in clinical trials involving patients with RLS Pediatric Dose Contraindications Interactions Not established Documented hypersensitivity May potentiate dopaminergic side effects of levodopa and may cause or exacerbate pre19 Copyright@2002 existing dyskinesia (decreasing dose of levodopa may ameliorate this effect); estrogens may reduce clearance by 36% (dose adjustment may be required if estrogen therapy stopped or started during treatment with ropinirole); potential exists for substrates or inhibitors of CYP1A2 to alter clearance—if therapy with potent CYP1A2 inhibitor stopped or started during ropinirole treatment, dose adjustments may be necessary; dopamine antagonists such as phenothiazines, butyrophenones, thioxanthenes, and metoclopramide may diminish effectiveness Pregnancy C - Safety for use during pregnancy has not been established. Precautions Monitor for signs and symptoms of orthostatic hypotension; cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have occurred in some patients treated with ergot-derived dopaminergic agents— these complications do not always resolve completely when drug discontinued; because of possible additive sedative effects by CNS depressants, caution when administering ropinirole concomitantly Drug Category: Benzodiazepines -- These agents may be used as monotherapy in patients with mild or intermittent symptoms or as combination therapy in severe cases. Clonazepam (Klonopin) has been shown to ease sensory symptoms and PLMS in RLS. Other benzodiazepines, such as temazepam (Restoril) and alprazolam (Xanax) also can be effective. Drug Name Clonazepam (Klonopin) -- No controlled trials have demonstrated that clonazepam or any other GABAergic sedative hypnotic actually reduces symptoms of RLS. Therapeutic benefit appears to arise from sleep-promoting properties such that patient continues to sleep despite disturbances from RLS symptoms. Adult Dose 0.25 mg PO qhs initially; increase daily dose by 0.25 mg each wk; not to exceed 2.0 mg/d Pediatric Dose Contraindications Not established Documented hypersensitivity; severe liver disease; acute narrow-angle glaucoma Interactions Phenytoin and barbiturates may reduce effects; CNS depressants increase toxicity Pregnancy C - Safety for use during pregnancy has not been 20 Copyright@2002 established. Precautions Major adverse effects include daytime drowsiness and confusion, unsteadiness leading to falls, and aggravation of sleep apnea; caution in chronic respiratory disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation of medication Drug Category: Opioids -- Low-potency opioids, such as codeine and propoxyphene (Darvon, Dolene), can benefit patients with mild and intermittent symptoms; higher-potency agents, such as oxycodone hydrochloride (Roxicodone), methadone hydrochloride (Dolophine), and levorphanol tartrate (LevoDromoran), may have a role in refractory cases. Because of the risk of addiction, these drugs should be used with caution; their use usually is recommended only in refractory cases. Drug Name Codeine -- This and other opioids can be helpful in decreasing symptoms of RLS as treatment of second choice when other treatments have failed or caused augmentation problems. Adult Dose 15 mg PO qhs prn Pediatric Dose Contraindications Not established Documented hypersensitivity; HACE; elevated ICP Interactions Tricyclic antidepressants, MAOIs, neuromuscular blockers, CNS depressants, phenothiazines, and narcotic analgesics increase toxicity Pregnancy C - Safety for use during pregnancy has not been established. Precautions Use to treat cough in patients with HACE only if absolutely necessary; may depress hypoxic ventilatory rate and respiratory drive during sleep Drug Category: Anticonvulsants -- These agents are used to manage severe muscle spasms. Drug Name Gabapentin (Neurontin) -- Indicated for patients whose symptoms include pain and/or neuropathy. May be used as single treatment or with other treatments. Adult Dose 100-300 mg PO qhs initially; increase by 100-300 mg q3d to maximum 2400 mg/d divided tid Pediatric Dose Contraindications Interactions Not established Documented hypersensitivity Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly 21 Copyright@2002 Pregnancy C - Safety for use during pregnancy has not been established. Precautions Usually well tolerated, but may cause transient or mild effects such as somnolence, dizziness, ataxia, and fatigue; caution in severe renal disease Drug Category: Presynaptic alpha2-adrenergic agonists -- These agents stimulate alpha2adrenoreceptors in brain stem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow. Drug Name Clonidine hydrochloride (Catapres) -- May be effective in primary RLS and that associated with uremia. However, has no effect on PLMS. Adult Dose Initial dose: 0.1 mg PO qhs; can increase daily dose weekly by 0.1 mg; not to exceed 1 mg/d; average effective dose is 0.5 mg/d Pediatric Dose Contraindications Not established Documented hypersensitivity Interactions Tricyclic antidepressants inhibit hypotensive effects; beta-blockers may potentiate bradycardia; tricyclic antidepressants may enhance hypertensive response associated with abrupt clonidine withdrawal; narcotic analgesics increase hypotensive effects of clonidine Pregnancy C - Safety for use during pregnancy has not been established. Precautions Common adverse effects include dry mouth, decreased cognition, light-headedness, sleepiness, and constipation; caution in cerebrovascular disease, coronary insufficiency, sinus node dysfunction, and renal impairment 22 Copyright@2002 Restless Legs Syndrome: Detection and Management in Primary Care NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WORKING GROUP ON RESTLESS LEGS SYNDROME National Institutes of Health, Bethesda, Maryland Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep complaint. Patients with RLS have an irresistible urge to move their legs, which is usually due to disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. It is estimated that between 2 and 15 percent of the population may experience symptoms of RLS. Primary RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency, neurologic lesions, pregnancy and uremia. RLS also may occur secondarily to the use of certain medications. The diagnosis of RLS is based primarily on the patient's history. A list of questions that may be used as a basis to assess the likelihood of RLS is included in this article. Pharmacologic treatment of RLS includes dopaminergic agents, opioids, benzodiazepines and anticonvulsants. The primary care physician plays a central role in the diagnosis and management of RLS. (Am Fam Physician 2000;62:108-14.) Restless legs syndrome (RLS) is a common, underdiagnosed and treatable condition. A neurologic movement disorder, RLS is often associated with a sleep complaint.1 Patients with RLS may suffer an almost irresistible urge to move the legs, usually due to disagreeable leg sensations that are worse during inactivity and often interfere with sleep.2 RLS may be described as an agitated inability to rest that can have a negative impact on quality of life by causing waking discomfort, chronic sleep deprivation and stress. This article provides science-based information about RLS and its assessment and management in the primary care setting. Consequences of RLS Direct adverse effects of RLS include discomfort, sleep disturbances and fatigue.3 These consequences have a secondary impact on functioning by affecting occupational activities, social activities and family life. Disrupted sleep and an inability to tolerate sedentary activities can lead to job loss, a compromised ability to enjoy life and problems with relationships. Prevalence RLS is a common disorder. Although the exact prevalence is uncertain, limited studies have indicated that 2 to 15 percent of the population may experience RLS symptoms.4-6 This wide range of results may be due to differences in study methodologies. Although the prevalence of RLS increases with age,6 it has a variable age of onset and can occur in children.7 In patients with severe RLS, one third to two fifths had their first symptom before 20 years of age,8 although the precise diagnosis of RLS was made much later. Etiology Primary RLS RLS is a central nervous system disorder.9 It is not caused by psychiatric factors or by stress but may contribute to or be exacerbated by these conditions. There is a high incidence of familial cases of RLS, suggesting a genetic origin for primary RLS.8 The exact mode of inheritance is unknown.8,10 23 Copyright@2002 Secondary Causes of RLS Iron Deficiency. RLS may be associated with iron deficiency. A patient's iron stores may be deficient without significant anemia. Recent studies have shown that decreased iron stores (indicated by serum ferritin levels below 50 ng per mL [50 µg per L] can exacerbate RLS symptoms.11,12 Patients with newly diagnosed RLS or RLS patients with a recent exacerbation of symptoms should have their serum ferritin levels measured. Secondary causes of restless legs syndrome include iron deficiency, spinal cord and peripheral nerve lesions, pregnancy, uremia and some medications. Neurologic Lesions. RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. RLS also may occur in patients with vertebral disk disease.8 Pregnancy. RLS affects up to 19 percent of women during pregnancy.13 Symptoms can be severe but usually subside within a few weeks postpartum. Uremia. RLS occurs in up to 50 percent of patients with end-stage renal failure and may be particularly bothersome during dialysis when the patient is confined to a resting position.14,15 Improvement in symptoms of RLS has been seen after renal transplantation.16 Drug-Induced. Some evidence from published case reports indicates that RLS symptoms may be induced or exacerbated by medications such as tricyclic antidepressants,17 selective serotonin reuptake inhibitors (SSRIs),18 lithium19 and dopamine antagonists.20 Caffeine also has been implicated in the worsening of RLS symptoms.21 Assessment and Diagnosis The diagnosis of RLS is based primarily on the patient's history. Often, patients do not bring RLS symptoms to the physician's attention; therefore, it can be helpful to include general sleep questions in the review of systems (Table 1). When RLS is suspected, more specific questions should be asked (Table 2). 24 Copyright@2002 TABLE 1 Sleep/Wake Profile TABLE 2 Questions That May Aid in the Diagnosis of Restless Legs Syndrome (RLS) How has the patient been sleeping recently? (Ask the patient and bed partner.) Suggested questions following a sleep complaint When did the problem begin? (To determine acute vs. chronic insomnia) Does the patient have a psychiatric or medical condition that may cause insomnia? Is the sleep environment conducive to sleep? (Relates to noise, interruptions, temperature, light) Does the patient report "creeping, crawling or uncomfortable, difficult-to-describe feelings" in the legs or arms that are relieved by moving them? (Relates to restless legs syndrome) Does the bed partner report that the patient's legs or arms jerk during sleep? (Relates to periodic limb movements of sleep) Does the patient snore loudly, gasp, choke or stop breathing during sleep? (Relates to obstructive sleep apnea) Is the patient a shift worker? What are the work hours? (Relates to circadian sleep disorders/sleep deprivation) What times does the patient go to bed and get up on weekdays and weekends? (Relates to poor sleep hygiene and sleep deprivation) Does the patient use caffeine, tobacco or alcohol? Does the patient take over-the-counter or prescription medications, such as Does the patient report "creeping, crawling or uncomfortable, difficult-to-describe feelings" in the legs or arms that are relieved by moving or rubbing them? Is there a correlation between RLS symptoms and time of day? Do the symptoms worsen with rest or inactivity? Do sensations interfere with sleep onset or returning to sleep? What daytime consequences does the patient report (e.g., fatigue, sleepiness, confusion, lack of attention)? Does the bed partner report that the patient's legs or arms jerk during sleep? (Relates to periodic limb movements of sleep.) Does the patient have secondary causes of RLS, such as low iron stores, diabetes mellitus, kidney disease or pregnancy? Are neurologic symptoms or diagnoses present? Is there a relationship between symptoms and medications, such as tricyclic antidepressants or selective serotonin reuptake inhibitors? Was the onset of symptoms correlated with a change in medication? Do family members report similar symptoms? Have any family members been diagnosed with RLS? 25 Copyright@2002 stimulating antidepressants, steroids, decongestants or betablockers? (Relates to substanceinduced insomnia) Signs of sleepiness What daytime consequences, such as fatigue, sleepiness, confusion or difficulty concentrating, does the patient report? Does the patient report dozing off or have difficulty staying awake during routine tasks, especially while driving? Symptoms are described by patients in many ways, with descriptions ranging from "mild" to "intolerable" (Table 3).22 Although most patients experience the sensations in their legs, the sensations also may occur in the arms or elsewhere. RLS symptoms are generally worse in the evening and night and less severe in the morning. RLS must be distinguished from sleep-related leg conditions such as nocturnal leg cramps. Clinical Criteria The criteria for the diagnosis of RLS are based on those developed by the International Restless Legs Syndrome Study Group (Table 4).3 The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also known as PLMS (periodic limb movements of sleep)23 or nocturnal myoclonus,24 which may be associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds. The most common movement is a dorsiflexion of the ankles and flexion of the knees or hips. 26 Copyright@2002 TABLE 3 Terms Used to Describe Sensations of Restless Legs Syndrome Creeping Crawling Itching Burning Searing Tugging Indescribable Pulling Drawing Aching Like water flowing Like worms or bugs crawling under the skin Like an electric current Restless Painful TABLE 4 Clinical Criteria and Associated Features of Restless Legs Syndrome (RLS) Minimal criteria A compelling urge to move the limbs, usually associated with paresthesias/dysesthesias Motor restlessness as seen in activities such as floor pacing, tossing and turning in bed and rubbing the legs Symptoms that are worse or exclusively present at rest (i.e., lying, sitting) with variable and temporary relief by activity Symptoms that are worse in the evening and at night Associated features Sleep disturbance and daytime fatigue Normal neurologic examination (in patients with primary RLS) Involuntary, repetitive, periodic, jerking limb movements, either in sleep or while awake and at rest Information from Waters AS. Toward a better definition of the restless leg syndrome. Mov Disord 1995; 10:634-42. Physical Examination The physical examination is usually normal in patients with RLS and is performed to identify secondary causes and to rule out other disorders. The following are areas of particular importance: A neurologic examination with emphasis on spinal cord and peripheral nerve function. A vascular examination to rule out vascular disorders. 27 Copyright@2002 Laboratory Tests The following laboratory tests can identify possible secondary causes of RLS: Serum ferritin level of <50 ng per mL (<50 µg per L). Serum chemistry to rule out uremia and diabetes. A sleep study (polysomnography) is not routinely indicated in the work-up of RLS,25 because RLS is diagnosed on the basis of history and clinical findings. Differential Diagnosis Differential diagnoses may include the following: Periodic limb movements of sleep (PLMS), also known as nocturnal myoclonus, may be associated with restless legs syndrome. Nocturnal leg cramps are typically painful, palpable, involuntary muscle contractions, often focal, with a sudden onset; they are usually unilateral.26 Akathisia is excessive movement, without specific sensory complaints; it often does not correlate with rest or time of day and usually results from medication such as neuroleptics or other dopamine blocking agents.27 Peripheral neuropathy can cause leg symptoms that are different from RLS; they are usually not associated with motor restlessness or helped by movement, and do not worsen in the evening or nighttime. Sensory complaints are typically numbness, tingling or pain. Small fiber sensory neuropathies, as seen in diabetes, are often confused with RLS. Patients with neuropathies may have neuropathic and RLS symptoms. Vascular disease, such as deep venous thrombosis. Treatment The severity of RLS varies from patient to patient. Although pharmacologic treatment is helpful for many patients with RLS, those with mild symptoms may not need medications. Because no single medication or combination of medications will work predictably for all patients, treatment must be individualized. Physicians and patients may need to work together over time to find the medication or combination of medications and the dosages that will work best. Table 5 lists appropriate pharmacologic agents and their advantages and disadvantages. Therapy for RLS constitutes an "offlabel" use of these pharmacologic agents. The selection of pharmacologic agents is influenced by a number of factors, including: Age of the patient. For example, benzodiazepines may cause cognitive impairment in the elderly. Severity of symptoms. Some patients with mild symptoms may elect not to use medications; others may benefit from levodopa or a dopamine agonist. Patients with severe symptoms may require a strong opioid. 28 Copyright@2002 Although many nonpharmacologic treatments have been reported by patients to be helpful, there is no scientific evidence to show that they are useful in the treatment of restless legs syndrome. Frequency or regularity of symptoms. Patients with infrequent symptoms may benefit from a single effective dose of a medication such as an opioid or levodopa, taken as needed. Presence of pregnancy or comorbid illnesses. No controlled clinical trials have assessed the safety and efficacy of medications for RLS or PLMS during pregnancy.28 Renal failure. In patients with renal failure, pharmacologic agents are generally safe, but less frequent doses may be needed if drugs are renally excreted. In addition, for dialysis patients, some medications, such as gabapentin, are dialyzable and others, such as propoxyphene, are not.28 Dopaminergic agents are the first-line drugs for most RLS patients. It is important for primary care physicians to educate patients about the nature and actions of the drugs that are prescribed, including side effects and the uncertainty of long-term effects. For example, when dopaminergic agents are prescribed, patients should be informed that although these medications are usually used to treat Parkinson's disease, they also help to relieve RLS symptoms. RLS medications have received approval from the U.S. Food and Drug Administration for other uses. In many cases, the therapeutic dosages to treat RLS are much lower than those required for the original uses. The starting dose is usually very low and is gradually increased until effective. In addition to the medications listed in Table 5, agents such as vitamin E, folate and magnesium may be useful. Although many nonpharmacologic treatments have been reported by patients to be helpful, there is no scientific evidence that they are useful in the treatment of RLS. 29 Copyright@2002 TABLE 5 Pharmacologic Treatment for Patients with Restless Legs Syndrome (RLS) Agent Advantages Disadvantages Dopamine precursor combinations such as carbidopalevodopa Can be used on a "one-time" basis or as circumstances may require. Useful for persons with intermittent RLS because dopamine agonists take longer to have an effect. As many as 80 percent of patients who take carbidopalevodopa may develop augmentation.* Therapeutic effect may be reduced if taken with high-protein food. Can cause insomnia, sleepiness and gastrointestinal problems. Dopamine agonists such as pergolide, pramipexole, ropinirole Useful in moderate to severe RLS. Recent reports indicate high efficacy of dopamine agonists, but the role of their long-term use is unknown.29 Can cause severe sleepiness,30 which may limit its use during daytime. Agonists can cause nausea. To avoid this, slow dosage increase is important, especially for pergolide. Opioids such as codeine, hydrocodone, oxycodone, propoxyphene, tramadol Can be used on an intermittent basis. Can also be used successfully for daily therapy. Can cause constipation, urinary retention, sleepiness or cognitive changes. Tolerance and dependence possible with higher doses of stronger agents. Benzodiazepines such as clonazepam, temazepam Helpful in some patients when other medications are not tolerated and may help improve sleep. Can cause daytime sleepiness and cognitive impairment, particularly in the elderly. Anticonvulsants such as Can be considered when dopamine agonists have failed. Vary, depending on agent. Gastrointestinal disturbance Dopaminergic agents 30 Copyright@2002 carbamazepine, gabapentin May be useful in those with coexisting peripheral neuropathy and/or when RLS discomfort is described as pain. such as nausea, sedation, dizziness. Iron (ferrous sulfate) Use in patients with serum ferritin levels <50 ng per mL (<50 µg per L). Ideal means of administration has not been established. Oral treatment may take several months to be effective and may be poorly tolerated. Clonidine May be useful in hypertensive patients. Has the potential to cause hypotension, dermatitis and sleepiness. *--Augmentation is a worsening of RLS symptoms in the course of therapy. Symptoms may be more severe and start earlier in the day (e.g., afternoon rather than evening) than before treatment began and may spread to different parts of the body. Augmentation, which can start soon after therapy is begun or not until months or years later, has also been reported with dopamine agonists and may occur with other medications. When to Consider Referral Most cases of RLS can be effectively managed by primary care physicians. If the primary care physician encounters difficulty managing RLS symptoms in a patient, referral to or consultation with a movement disorders specialist or a sleep specialist may be helpful. Conclusion The primary care physician plays a central role in the identification and treatment of RLS. Incorporating sleep- and RLS-related questions into the general review of systems can be helpful in diagnosing RLS. An important aspect of treatment is listening to and supporting patients and carefully evaluating their symptoms. Most patients with RLS can obtain symptomatic relief with commonly prescribed medications and support. 31 Copyright@2002 REFERENCES 1. 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