eMedicine Specialties > Neurology > Sleep-Related Diseases

Restless Legs Syndrome

Ali M Bozorg, MD, Assistant Professor, Comprehensive Epilepsy Program, Department of Neurology, University of South Florida

Updated: Aug 19, 2009

Introduction

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.^{[1 ]}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.^{[2 ]}Once correctly diagnosed, RLS can usually be treated effectively and in some secondary cases, it can even be cured.

Pathophysiology

The pathogenesis of RLS is unclear.^{[3,4,5 ]}Currently, the most widely accepted mechanism involves a genetic component along with abnormalities in the central, subcortical dopamine pathways and impaired iron homeostasis.^{[6,7 ]}When centrally acting dopamine receptor antagonists are administered to patients with the syndrome, symptoms are reactivated. Results of single-photon emission computed tomography (SPECT) have suggested deficiency of dopamine D2 receptors. Abnormalities of iron homeostasis have also been implicated, based on CSF iron profile measures.

RLS also has a genetic component and tends to run to in families.^{[8 ]}Various chromosomes have been implicated so far, including 12q, 14q, 9p, 20p, 4q, and 17p, in both autosomal dominant and recessive fashion.^{[6 ]}

Frequency

United States

RLS affects about 10-15% of the general population, with a female-to-male ratio of 2:1.^{[9 ]}The increased incidence of RLS in women is thought to be related to parity, and nulliparous women have the same risk of age-matched men.^{[10 ]}RLS is often unrecognized or misdiagnosed.^{[11,9 ]}Many patients are not diagnosed until 10-20 years after symptom onset. RLS 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, in some, may be severe enough to be disabling.

International

Although the exact prevalence is uncertain, limited studies have indicated that 2-15% of the population may experience symptoms of RLS.^{[1 ]}

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.^{[12,10 ]}

Race

RLS affects African Americans less commonly than white persons, even in secondary RLS caused by hemodialysis.

Sex

Women are affected more commonly than men at a ratio of almost 2:1. The increased risk of RLS in women is thought to be related to parity; nulliparous women have the same risk of developing RLS when compared to age-matched men.^{[10 ]}

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 symptoms and severe disruption of sleep after age 50 years. Individuals with familial RLS tend to have onset of symptoms before age 45 years.

Clinical

History

Diagnosis of restless legs syndrome (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 RLS Study Group in 1995; 4 basic elements must be present to make the diagnosis.^{[11,10,13 ]}They are as follows:^{[14 ]}
  • 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 worse or exclusively present at rest (ie, lying, sitting) with variable and temporary relief on activity
  • Circadian variation of symptoms that 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.)
• A positive response to dopaminergic therapy supports the diagnosis of RLS.
• Approximately 85% of patients with RLS have periodic leg movements of sleep (PLMS), usually involving the legs.^{[3 ]}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. PLMS noted on polysomnography alone do not warrant treatment. Clinicians should consider treating PLMS if they are causing frequent arousals.
• Other features commonly associated with RLS but not required for diagnosis include sleep disturbances, daytime fatigue, and involuntary, repetitive, periodic, jerking limb movements either during sleep or while awake and at rest. A positive family history also aids in the diagnosis, especially in children.

RLS in children

• RLS can be difficult to diagnose in children, especially younger children.^{[15 ]}In order to make the diagnosis of definite RLS, patients must endorse the 4 criteria of RLS and be able to describe leg symptoms in their own language.
• Alternatively, they must have the 4 essential criteria and have sleep disturbances, a sibling or parent with RLS, and a PLMS index >5 on polysomnography.^{[15 ]}For a possible diagnosis of RLS, a PLMS index >5 on polysomnography and a first-degree family member with RLS are required.
• These strict criteria are intended to prevent overdiagnosis of RLS in children.

Physical

The physical examination is usually normal in patients with RLS; it is performed to identify secondary causes and to exclude other disorders. In particular, the patient should be evaluated for neuropathy, radiculopathy, and parkinsonism.

Causes

RLS can be primary or secondary.

• Primary RLS
  • 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 or recessive inheritance (see Pathophysiology).
  • Progressive decrease in age at onset with subsequent generations (ie, genetic anticipation) has been described in some families. Patients with familial RLS tend to have an earlier age at onset (<45 y) and slower progression.
  • Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS.
• Secondary RLS^{[1 ]}
  • RLS can develop as a result of certain conditions or factors, particularly iron deficiency and peripheral neuropathy.^{[9 ]}These 2 conditions should be excluded before RLS is labeled as primary.^{[9 ]}Because of the prevalence of these conditions in the general population, their association with RLS needs to be interpreted with caution.
  • Other causes are folate or magnesium deficiency, amyloidosis, diabetes mellitus, lumbosacral radiculopathy, Lyme disease, monoclonal gammopathy of undetermined significance, rheumatoid arthritis, Sjögren syndrome, uremia, or vitamin B-12 deficiency.
  • Women can be affected by RLS during pregnancy, and the syndrome usually subsides within a few weeks after delivery. It affects 25-40% of pregnant women.
  • RLS also occurs in as many as 25-50% of patients who have end-stage renal disease and find their symptoms particularly bothersome during hemodialysis. One study found that hyperphosphatemia, anxiety, and a great degree of emotion-oriented coping with stress were independently related to the presence of RLS in patients with uremia who were taking hemodialysis therapy.^{[4 ]}
  • Certain medications can also cause RLS. Antidopaminergic medications (such as neuroleptics), diphenhydramine, selective serotonin reuptake inhibitors (SSRIs), alcohol, caffeine, lithium, and beta-blockers have been known to cause or exacerbate the symptoms of RLS.
• The pathogenesis of RLS seems to involve more than one mechanism, which leads to restless legs as the final common pathway.

Differential Diagnoses

Akathisia
Alcohol (Ethanol) Related Neuropathy
Neuropathy
Nocturnal leg cramps
Peripheral Vascular Disease
Radiculopathy

Other Problems to Be Considered

Neuropathy: Patients with neuropathy can have symptoms similar to those with restless legs syndrome (RLS).^{[16 ]}Typically, sensory complaints are numbness, tingling, or pain. Neuropathy causes symptoms that are somewhat different from those of RLS. Neuropathic symptoms usually are neither associated with motor restlessness nor helped by movement and do not worsen in evening or night time. Neuropathy and RLS may coexist. RLS occurs more frequently in patients with hereditary neuropathies but not in patients with acquired neuropathies such as diabetic neuropathy.^{[16 ]}

Nocturnal leg cramps: These are typically unilateral, painful, palpable, involuntary muscle contractions, which are 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: This is characterized by an inner urge to move part of or 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 selective serotonin reuptake inhibitors (SSRIs), neuroleptics, or other dopamine-blocking agents.^{[17 ]}

Painful legs and 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.

Vascular disease (including deep vein thrombosis and claudication): Patients with RLS have intact peripheral pulses. RLS is not associated with edema or cool extremities. Also, vascular disease does not exhibit a circadian pattern and usually worsens with activity, not rest.

Workup

Laboratory Studies

• All patients with symptoms of restless legs syndrome (RLS) should be tested for iron deficiency.^{[11,18 ]}At a minimum, a ferritin level should be obtained. A complete iron panel including iron levels, ferritin, transferrin saturation, and total iron binding capacity is preferable, since ferritin can be falsely elevated in acute inflammatory states. Patients who are well-controlled and develop re-emergence of symptoms (or augmentation) should undergo repeat evaluation of their iron status.
• If a secondary cause is suspected on the basis of history, abnormal findings on neurologic examination, or poor response to treatment, other laboratory tests should be done. These tests include measurement of levels of BUN, creatinine, fasting blood glucose, magnesium, thyroid-stimulating hormone (TSH), vitamin B-12, and folate, in addition to a CBC count.

Imaging Studies

• Imaging studies are not routinely used in the diagnosis of patients with RLS.

Other Tests

• Polysomnography may be necessary to quantify PLMS or to characterize sleep architecture, especially in children and in patients who continue to have significant sleep disturbances despite relief of RLS symptoms with treatment. Polysomnography should also be used in patients with other suspected sleep comorbidities.
• Needle electromyography and nerve conduction studies should be considered if polyneuropathy or radiculopathy is suspected on clinical grounds, even if the results of the neurologic examination are apparently normal.^{[19 ]}

Treatment

Medical Care

Treatment may not be necessary for patients with mild or sporadic symptoms or for those without significant impairment.^{[18 ]}Treatment should be tailored on the basis of the patient's specific symptoms.^{[18 ]}

• Nonpharmacologic management
  • Sleep hygiene measures should be recommended to all patients.
  • Patients with mild RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Offending medications such as SSRIs, diphenhydramine, and dopamine antagonists also should be discontinued when possible.
  • Exercise may be helpful for some patients; however, this has not been systemically studied. In general, physical measures are only partially or temporarily helpful and should be avoided prior to bedtime.
  • 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.
  • Nonpharmacological management and sleep hygiene measures is the treatment of choice in children. A regular sleep/wake schedule and the elimination of stimulating activity and caffeine prior to bedtime are important measures.

Diet

Patients with RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances.

Medication

Drug therapy for primary restless legs syndrome (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.

All patients with low iron levels (ferritin <50 ng/mL) should receive supplemental iron therapy.^{[18 ]}In iron deficiency, 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.

Pharmacotherapy in children

No specific recommendations exist for the treatment of RLS in children. Children with low serum ferritin (<50 ng/mL) should be treated with supplemental iron therapy. No FDA-approved medications are available for the treatment of RLS in children. Dopaminergic therapy has been used in small series in children with RLS and has been shown to be effective.

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. They 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. Levodopa/carbidopa is generally reserved for patients with infrequent symptoms because of problems with augmentation and rebound.

Rotigotine (Neupro)

Dopamine agonist stimulating D3, D2, and D1 receptors. Improvement in Parkinson-related symptoms thought to be its ability to stimulate D2 receptors within the caudate putamen in the brain. Available as transdermal patch that provides continuous delivery for 24 h (2 mg/24 h [10 cm²], 4 mg/24 h [20 cm²], or 6 mg/24 h [30 cm²]). Indicated for symptoms of early Parkinson disease only. Rotigotine is not FDA-approved for the treatment of RLS but has been shown to be effective in the treatment of RLS.^{[21 ]}Rotigotine was withdrawn from US markets in March of 2008 secondary to crystallization of the drug in the patch.

Dosing

Adult

1 mg/24 h (10 cm²) transdermal qd initially; may increase qwk by 2 mg/24 h, not to exceed 3 mg/24 h

Remove previous day's patch before applying new patch; rotate application site each day between left and right sides of body and upper and lower parts of body

Pediatric

Indication not applicable to children

Interactions

Dopamine antagonists (eg, antipsychotics, metoclopramide) may decrease effect

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include dermal reactions at patch site, dizziness, nausea, vomiting, drowsiness, and insomnia; less common adverse effects that may be hazardous to patient include sudden sleep onset, hallucinations, and postural hypotension; weight gain secondary to fluid retention has been observed; rapid dose reduction or abrupt withdrawal may cause hyperpyrexia and confusion; apply to clean, dry, and intact skin on abdomen, thigh, hip, flank, shoulder, or upper arm

Pramipexole (Mirapex)

D2 and D3 receptor agonist recently approved by FDA for treating Parkinson disease; also used effectively in patients with RLS.^{[20 ]}

Dosing

Adult

0.125-1.0 mg PO pm or hs

Pediatric

Not established

Interactions

Cimetidine may increase toxicity; increases levodopa levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal insufficiency and pre-existing dyskinesias; cases of rhabdomyolysis have been reported in patients with advanced Parkinson disease treated with pramipexole

Ropinirole hydrochloride (Requip)^{[13 ]}

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.

Dosing

Adult

0.5-5.0 mg PO am or hs

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

Not established

Interactions

May potentiate dopaminergic side effects of levodopa and may cause or exacerbate pre-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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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 mg (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. Sinemet is preferred for patients with occasional and mild symptoms.

Dosing

Adult

25/100-50/200 mg PO qhs

Pediatric

Not established

Interactions

Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects of levodopa; levodopa toxicity increases with antacids and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; MAOI use within last 14 d; melanoma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Certain adverse CNS effects (eg, 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

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.

Dosing

Adult

7.5 mg PO qd am and hs

Pediatric

Not established

Interactions

Ergot alkaloids may increase toxicity; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, reserpine may decrease effects

Contraindications

Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in renal or hepatic disease

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.

Dosing

Adult

0.1-0.5 mg/d PO am and hs

Pediatric

Not established

Interactions

Dopamine antagonists such as neuroleptics, phenothiazines, butyrophenones, thioxanthenes, 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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

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.

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.

Dosing

Adult

0.25 mg PO qhs initially; increase daily dose by 0.25 mg each wk; not to exceed 2.0 mg/d

Pediatric

Not established

Interactions

Phenytoin and barbiturates may reduce effects; CNS depressants increase toxicity

Contraindications

Documented hypersensitivity; severe liver disease; acute narrow-angle glaucoma

Precautions

Pregnancy

C - Safety for use during pregnancy has not been 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

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 (Levo-Dromoran), 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, especially in ones with a prominent pain component.

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.

Dosing

Adult

15 mg PO qhs prn

Pediatric

Not established

Interactions

Tricyclic antidepressants, MAOIs, neuromuscular blockers, CNS depressants, phenothiazines, and narcotic analgesics increase toxicity

Contraindications

Documented hypersensitivity; HACE; elevated ICP

Precautions

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

Anticonvulsants

These agents are being used more frequently for the treatment of moderate to severe RLS. They are particularly helpful in patients with a strong neuropathic component of symptoms or with comorbid neuropathy.

Gabapentin (Neurontin)

Indicated for patients whose symptoms include pain and/or neuropathy. May be used as single treatment or with other treatments.

Dosing

Adult

100-300 mg PO qhs initially; increase by 100-300 mg q3d to maximum 2400 mg/d divided tid

Pediatric

Not established

Interactions

Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly

Contraindications

Documented hypersensitivity

Precautions

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

Pregabalin (Lyrica)

Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha₂ -delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures. Pregabalin is NOT FDA-approved for the treatment of RLS.

Dosing

Adult

50 mg PO qhs, can increase to 150 mg PO qhs

Pediatric

Not established

Interactions

May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min); angioedema has been reported during postmarketing surveillance

Presynaptic alpha2-adrenergic agonists

These agents stimulate alpha2-adrenoreceptors in brain stem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow.

Clonidine hydrochloride (Catapres)

May be effective in primary RLS and that associated with uremia. However, has no effect on PLMS.

Dosing

Adult

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

Not established

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

Contraindications

Documented hypersensitivity

Precautions

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

Follow-up

Further Outpatient Care

• Patients should be monitored by a neurologist or their primary care provider for development of adverse events, augmentation, or rebound.

Patient Education

• Education of patients and their families should focus on providing a better understanding of the disease and the importance of compliance in improving the symptoms.
• For excellent patient education resources, visit eMedicine's Sleep Disorders Center. Also, see eMedicine's patient education articles Restless Legs Syndrome, Sleep Disorders in Women, and Sleep Disorders and Aging.

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Keywords

RLS, Ekbom syndrome, Ekbom's syndrome, restless legs, movement disorder of the limbs, sleep disorder, sleep complaint, restlessness in the legs, insomnia, primary RLS, secondary RLS, restless legs syndrome

Contributor Information and Disclosures

Author

Ali M Bozorg, MD, Assistant Professor, Comprehensive Epilepsy Program, Department of Neurology, University of South Florida
Ali M Bozorg, MD is a member of the following medical societies: American Academy of Neurology and American Academy of Sleep Medicine
Disclosure: Nothing to disclose.

Medical Editor

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center Florida Center for Neurology
Erasmo A Passaro, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association, and American Society of Neuroimaging
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Juan Latorre, MD, and William G Irr, MD, to the development and writing of this article.

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