Abstract
Abbreviations and Acronyms:
MAB (Medical Advisory Board), RLS (restless legs syndrome), WED (Willis-Ekbom disease)- Garcia-Borreguero D.
- Ferini-Strambi L.
- Kohnen R.
- et al.
- Aurora R.N.
- Kristo D.A.
- Bista S.R.
- et al.
Intermittent RLS/WED

Nonpharmacological Strategy
- •Determining the patient’s iron status (early-morning fasting iron panel: iron, serum ferritin, total iron-binding capacity, and percentage of iron saturation). If the iron stores are low, administer iron replacement (see subsequent comment 1).
- •Recommend mental alerting activities, such as video games or crossword puzzles, to reduce symptoms at times of boredom (see subsequent comment 2).
- •Consider a trial of abstinence from caffeine (see subsequent comment 2).
- •Consider whether antidepressants, neuroleptic agents, dopamine-blocking antiemetics (such as metoclopramide), or sedating antihistamines (including those found in nonprescription medications) may be contributing and whether discontinuation is possible without causing the patient harm (see subsequent comment 2).
- 1.Because RLS/WED may be the only clinical indication of iron deficiency, clinicians should consider evaluating the iron status in all patients with RLS/WED, especially those with a history of gastrointestinal blood loss, disorders or medications predisposing to gastrointestinal blood loss, menorrhagia, frequent blood donation, or recent onset or worsening of symptoms. If the serum ferritin concentration is in the abnormal range (usually <20 μg/L [to convert to pmol/L, multiply by 2.25] but adjusted based on age, sex, and the normative data from the specific laboratory) or percentage of iron saturation is low (<18%), a cause of iron deficiency should be pursued and replacement treatment instituted. A serum ferritin concentration lower than 45 to 50 μg/L has been associated with an increased severity of RLS/WED,25,26and treatment of patients with ferritin levels less than 75 μg/L has been shown to improve symptoms.27Therefore, therapy can be attempted in patients with levels in this low-normal range on a case-by-case basis. Note that serum ferritin is an acute-phase reactant and can be falsely elevated in the presence of acute infection or chronic inflammation. A common therapeutic regimen is 325 mg of ferrous sulfate (65 mg of elemental iron) combined with 100 to 200 mg of vitamin C with each dose to enhance absorption 2 to 3 times a day. Oral iron therapy can cause constipation and abdominal discomfort, and the dose may need to be reduced in some patients, requiring a longer duration of therapy. Iron tablets should ideally be taken on an empty stomach to enhance absorption, but if gastrointestinal symptoms develop, they can be taken with food. Iron should not be prescribed empirically because it may result in iron overload, especially in patients with previously unsuspected hemochromatosis. Follow-up ferritin level determinations are needed, initially after 3 to 4 months and then every 3 to 6 months until the serum ferritin level is greater than 75 μg/mL and the percentage of iron saturation is greater than 20%.28Iron therapy can then be discontinued if an ongoing cause for iron deficiency has not been established. However, follow-up serum ferritin level determinations to ensure that levels do not decrease are recommended at least every 1 to 2 years, and earlier if RLS/WED symptoms worsen. Note that patients with RLS/WED do not always respond to an increasing serum ferritin concentration, even if it was low initially.
- 2.The recommendations to engage in mental alerting activities and to consider a trial of abstinence from caffeine are largely based on clinical experience rather than on scientific studies.
- 3.Clinical experience suggests that most antidepressant agents may sometimes be associated with initiation or worsening of RLS/WED. However, if antidepressants are deemed necessary, the symptoms can usually be treated in the same way as primary RLS/WED. Alternatively, use of bupropion can be considered because this antidepressant with dopamine agonist properties does not seem to induce or worsen RLS/WED.29
Comments
- 1.
Medication
- •Carbidopa/levodopa, 25 mg/100 mg, or the controlled-release formulation, 25 mg/100 mg (see subsequent comment 4)
- •Low-potency opioids, such as codeine, or opioid agonists, such as tramadol (see subsequent comment 5)
- •Benzodiazepines or benzodiazepine agonists, such as temazepam, zolpidem, zaleplon, or eszopiclone (see subsequent comment 6)
- 4.Carbidopa/levodopa, 25 mg/100 mg (0.5-1.0 tablets), can be used for RLS/WED that occurs intermittently in the evening, at bedtime, or on waking during the night or for RLS associated with specific activities, such as airplane or lengthy car rides or theater attendance. Controlled-release carbidopa/levodopa, 25 mg/100 mg (1 tablet), can be used alternatively at bedtime for RLS that awakens the patient during the night. Even the controlled-release form has a relatively short duration of action and may not produce sustained efficacy if RLS/WED persists throughout much of the night. Controlled trials have shown the efficacy of both preparations.23For maximal absorption, levodopa should not be taken with high-protein foods.
- Aurora R.N.
- Kristo D.A.
- Bista S.R.
- et al.
The treatment of restless legs syndrome and periodic limb movement disorder in adults: an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.Sleep. 2012; 35: 1039-1062Problems with levodopa treatment include augmentation and rebound. Augmentation (see subsequent comment 7) may occur in up to 70% of patients taking levodopa daily, and the risk increases with daily doses of 200 mg or more.30As a result, levodopa should be prescribed only for intermittent use, such as fewer than 3 times a week, although a lower risk of augmentation with such use has not been firmly established. Rebound, the recurrence of RLS/WED in the early morning, occurs in 20% to 35% of patients taking levodopa.31(Because the action of dopamine agonists generally commences 90 to 120 minutes after ingestion, these agents cannot be used effectively once symptoms have started, and they are rarely prescribed for intermittent RLS/WED.) - 5.Intermittent use of low-potency opioids or opioid receptor agonists, usually at bedtime, can be effective. Doses of 30 to 60 mg of codeine, usually available in combined preparations with acetaminophen, or 50 to 100 mg of tramadol can be taken at bedtime or during the night. Constipation or nausea may occur. Tramadol can rarely induce seizures, and it is the only nondopaminergic drug associated occasionally with the development of augmentation.
- 6.Intermittent use of benzodiazepines or benzodiazepine receptor agonists before sleep may be useful, especially if the patient has another cause of poor sleep in addition to RLS/WED, such as psychophysiologic insomnia. Short-acting agents, such as zolpidem (5-10 mg) and zaleplon (5-10 mg), may be helpful for sleep-onset insomnia caused by RLS/WED; intermediate-acting agents, such as temazepam (15-30 mg) and eszopiclone (1-3 mg), may be helpful for RLS/WED that awakens the patient later in the night. Long-acting agents, such as clonazepam, may result in more adverse effects, such as impotence in older men, unsteadiness during the night, and drowsiness or cognitive impairment in the morning, and should generally be avoided. There are no adequate controlled trials of benzodiazepines for RLS/WED,23and it is likely that the drugs act by treating the associated insomnia rather than the sensory or motor symptoms of the disorder.
- Aurora R.N.
- Kristo D.A.
- Bista S.R.
- et al.
The treatment of restless legs syndrome and periodic limb movement disorder in adults: an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.Sleep. 2012; 35: 1039-1062
Comments
- 4.
Chronic Persistent RLS/WED

Nonpharmacological Strategy
Medication
- •A nonergot dopamine agonist (pramipexole, ropinirole, or the rotigotine patch) (see subsequent comment 7)
- •An α-2-δ calcium channel ligand (gabapentin, pregabalin, or gabapentin enacarbil) (see subsequent comment 8)Table 1 lists clinical features that should be considered in the choice of an initial drug.24Because the α-2-δ ligands can cause depression and weight gain, a dopamine agonist is a more appropriate choice in the presence of these conditions. α-2-δ Ligands can alleviate chronic pain and may be helpful in treating anxiety and insomnia,32so the presence of any of these comorbidities may favor their use. For restless legs present through much of the day and night, consider the use of long-acting agents, such as the rotigotine patch or gabapentin enacarbil.
- 7.Nonergot dopamine agonists (Table 2) should be used because ergot agonists, such as cabergoline, are associated with cardiac valvular fibrosis and other fibrotic reactions.22,
- Garcia-Borreguero D.
- Ferini-Strambi L.
- Kohnen R.
- et al.
European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society.Eur J Neurol. 2012; 19: 1385-139623Pramipexole is usually commenced as 0.125 mg once daily, taken 2 hours before major RLS symptoms start. The dose is increased by 0.125 mg every 2 to 3 days until relief is obtained. Most patients require 0.5 mg or less, and patients taking higher doses should be carefully monitored for adverse effects, especially augmentation (see later herein). Experts differ on an acceptable maximum daily dose, but most agree that this should not exceed 0.75 or 1.0 mg. Ropinirole is usually commenced as 0.25 to 0.5 mg taken 1.5 hours before major symptoms start and is increased by 0.25 to 0.5 mg every 2 to 3 days. Most patients require 2 mg or less (note that 4-times higher equivalent doses are needed compared with pramipexole), but total daily dosages up to 4 mg may be needed. Some patients require twice-daily doses of oral agonists, with an earlier dose in the late afternoon or early evening and a second dose before going to bed. The rotigotine patch is applied once daily, commencing at 1 mg and increasing, if necessary, to 2 to 3 mg. Minor adverse effects of the agonists include nausea and light-headedness that usually resolve within 10 to 14 days. Nasal stuffiness, constipation, insomnia, and leg edema occur less frequently and are reversible with cessation of treatment. Hypersomnia and sleep attacks may occur, often at higher doses. Application site reactions may occur with the rotigotine patch.- Aurora R.N.
- Kristo D.A.
- Bista S.R.
- et al.
The treatment of restless legs syndrome and periodic limb movement disorder in adults: an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.Sleep. 2012; 35: 1039-106233Careful monitoring for adverse effects is essential, especially when higher doses are used.Table 2Comparison of Dopamine Agonists Used to Treat RLS/WEDVariable Pramipexole Ropinirole Rotigotine patch Time to maximum blood level (h) 2 1-1.5 Stable plasma levels over 24 h Elimination half-life (h) 8-12 (increases with decreasing glomerular filtration rate and age) 6 Stable plasma levels over 24 h (elimination half-life biphasic: 3 and 6) Metabolism and excretion Renal Hepatic metabolism and renal excretion Hepatic metabolism and renal excretion Initial daily dose (mg) 0.125 0.25 (–0.5) 1 Maximum daily dose (mg) 0.5 (–1.0) 4 3 a RLS = restless legs syndrome; WED = Willis-Ekbom disease.b Values in parentheses differ from Food and Drug Administration–approved values.Two major problems often limit the use of dopamine agonists. First, augmentation34(a worsening of RLS symptoms earlier in the day after an evening dose of medication, including earlier onset of symptoms, increased intensity of symptoms, or spread of symptoms to the arms) occurs in 40% to 70% of patients using pramipexole for up to 10 years- García-Borreguero D.
- Allen R.P.
- Kohnen R.
- et al.
Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute.Sleep Med. 2007; 8: 520-53012and probably a similar percentage with ropinirole. The frequency of augmentation with the rotigotine patch may be slightly lower at 36%.15Second, 6% to 17% of patients experience impulse control disorders, such as pathologic gambling, impulsive shopping, or hypersexuality.13,24These symptoms commence an average of 9 months after introduction of the drug, so patients should be questioned about them at every follow-up visit. - 8.Gabapentin and pregabalin (Table 3) are usually administered as once- or twice-daily doses in the late afternoon or evening or before sleep. Treatment should commence at 300 mg of gabapentin or 100 mg of pregabalin daily and should be increased every few days as needed. Many patients require 900 to 1800 mg of gabapentin daily, but doses up to 3600 mg/d can be used. Because of nonlinear kinetics, the gabapentin dose does not always reflect the serum level. Effective pregabalin doses are usually in the range of 150 to 450 mg/d. Gabapentin enacarbil is a prodrug of gabapentin, converted to gabapentin after absorption. It is administered as a single daily dose of 600 mg at 5 pm. Doses of 1200 mg have been used. Class-specific adverse effects include drowsiness, dizziness, unsteadiness, weight gain, and depression. Patients should be carefully monitored for the development of adverse effects, especially if higher doses are used.22,
- Garcia-Borreguero D.
- Ferini-Strambi L.
- Kohnen R.
- et al.
European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society.Eur J Neurol. 2012; 19: 1385-139623- Aurora R.N.
- Kristo D.A.
- Bista S.R.
- et al.
The treatment of restless legs syndrome and periodic limb movement disorder in adults: an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.Sleep. 2012; 35: 1039-1062Table 3Comparison of α-2-δ Agents Used to Treat RLS/WEDVariable Gabapentin Pregabalin Gabapentin enacarbil Time to maximum blood level (h) 2 1.5 7-9 Elimination half-life (h) 5-7 6 Relatively stable plasma levels over 18-24 h (elimination half-life: 6) Metabolism and excretion Renal Renal Intestinal metabolism and renal excretion Initial daily dose (mg) 300 100 600 Maximum daily dose (mg) 3600 450 600 (–1200) a RLS = restless legs syndrome; WED = Willis-Ekbom disease.b Value in parentheses differs from the Food and Drug Administration–approved value. - 9.If augmentation develops with dopamine agonists, consider initially splitting the dose with some of the drug administered earlier in the day.24(Use of extended-release pramipexole or ropinirole can be considered, generally without increasing the total daily dose, although there are no data available on their use in RLS/WED.) If an increase in the total dose of agonist is deemed necessary, careful monitoring is essential to detect progressive augmentation, in which case the drug should be discontinued.
- 10.If the first drug is ineffective or poorly tolerated, consider a change to another agent in the same class.24In particular, consider the rotigotine patch if progressive augmentation has developed while taking pramipexole or ropinirole. However, careful monitoring is needed if class-specific adverse effects occurred with the first drug, and should these recur with the second drug, further agents in the same class should not be used.
- 11.If 1 or more drugs in the first class tried are ineffective or poorly tolerated, consider a change to an agent in the other class (an α-2-δ ligand for an agonist and vice versa). This can be achieved in 2 ways. The initial drug can be reduced slowly at the same time as the new agent is introduced, with an overlap period when the patient is taking both medications. Alternatively, the initial drug can be reduced and discontinued, with a drug holiday before introducing the new agent. Although this can allow for a new symptom baseline to be established, many patients find it hard to tolerate a period free of any medication. (Note that higher doses of dopamine agonists should never be discontinued abruptly because serious withdrawal effects can occur. Rates of reduction should not exceed 0.25 mg of pramipexole or 0.5 mg of ropinirole every 3 days.)
Comments
Table 1Clinical Features Guiding Choice of Initial Agent for Chronic Persistent RLS/WEDDopamine agonists α-2-δ Ligands Very severe RLS/WED Comorbid pain Comorbid depression or dysthymia Comorbid anxiety Obesity/metabolic syndrome Comorbid insomnia Previous impulse control disorder or addiction RLS = restless legs syndrome; WED = Willis-Ekbom disease. - 7.
Refractory RLS/WED

- •Iron stores should be rechecked. If the serum ferritin level is less than 50 to 75 μg/L, oral iron supplementation should be prescribed. If this does not result in increasing serum ferritin levels owing to malabsorption or if oral iron intake is not tolerated, intravenous administration of iron should be considered (see subsequent comment 12).
- •Other exacerbating factors should be sought, including the use of antihistamines or other medications that can worsen restless legs (see the “Intermittent RLS/WED” section), change in lifestyle (such as more sedentary behavior or shift work), or other causes of sleep disturbance, such as sleep apnea or chronic insufficient sleep.
- •Consider combination therapy with drugs of different classes. Add a second agent and try to reduce the dose of the initial drug. Second agents may include a dopamine agonist for patients treated with an α-2-δ ligand or vice versa, a benzodiazepine (if restless legs are present mainly at night with resulting insomnia), or a low- or high-potency opioid. Usually, the initial agent is continued at the same dose, but it may be possible to reduce the dose with time (see previous comments 5 and 6).
- •Consider substituting a high-potency opioid, such as oxycodone, hydrocodone, or methadone. In particular, consider low-dose methadone for severe refractory RLS resistant to other treatments.12Daily effective doses of these drugs usually range from 5 to 20 mg in single or divided doses, depending on the time of symptoms. In some patients, a long-acting form of oxycodone may be most appropriate, but total daily doses should be kept low and should never approach the higher doses used for the management of chronic pain (see subsequent comment 13).
- 12.Intravenous iron should currently be restricted to patients with proven low or low-normal serum ferritin levels who are intolerant of oral iron or who are resistant to oral iron because of malabsorption. Iron gluconate, iron sucrose, iron dextran, and ferumoxytol are all infusion preparations available in the United States. Although iron dextran is associated with risk of anaphylaxis, the more recently developed low-molecular-weight iron dextran has a reduced incidence of anaphylactic reactions, estimated to be 1 per 200,000 infusions.35A trial of ferric carboxymaltose in patients with RLS/WED had positive results,17but the preparation is not currently available in the United States.
- 13.High-potency opioids may be highly effective in the management of RLS and should not be withheld from appropriate patients because of a fear of potential development of tolerance or dependence. Escalation of dose is uncommon, and dependence is infrequent in the absence of a history of substance abuse. Nausea and constipation are rare. Itch may be a problem due to mast cell degranulation rather than allergy. Daytime drowsiness, cognitive dysfunction, and unsteadiness resulting in falls, especially at night, are potential adverse effects. Opioids can precipitate or worsen obstructive sleep apnea and can induce central sleep apnea, especially in patients using continuous positive airway pressure (complex sleep apnea). Screening overnight oximetry or polysomnography should be considered for patients with RLS/WED taking opioids if there is a suspicion of sleep apnea. Generally, however, these medications are well tolerated at the recommended doses.
Comments
- 12.
Alternative, Investigative, and Potential Future Therapies
- Aurora R.N.
- Kristo D.A.
- Bista S.R.
- et al.
Conclusion
Acknowledgments
Supplemental Online Material
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Article Info
Footnotes
Potential Competing Interests: Dr Silber has received book royalties from Informa Healthcare and honorarium from Oakstone Publishing. Dr Becker has received financial support for research activities from Aerial Pharmaceuticals and UCB and for consulting activities from UCB and GSK and is a medical advisor and speakers’ bureau member for UCB. Dr Earley has received salary support from National Institutes of Health grant R01 NS075184 . Dr Garcia-Borreguero has received research grants from Pfizer and UCB and has been a consultant for UCB, Xenoport, Boehringer-Ingelheim, MSD, and Otsuka. Dr Ondo has been a speaker and consultant for Allergan, Merz, Ipsen, Lundbeck, Teva, UCB Pharma, and Novartis.