Restless legs syndrome

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment of primary restless legs syndrome (RLS) tends to be symptomatic. Treating the underlying cause in secondary RLS can potentially cure RLS.

Severity of symptoms can be graded using severity scales, but decision on treatment also depends on the impact of symptoms on the patient's sleep and quality of life.

General considerations in all patients

Assess iron status and consider appropriate iron replacement as needed.[23][26][28][34]

There is substantial evidence that patients with RLS have lower than normal iron stores in some regions of the brain and that iron treatment can be beneficial, even in the absence of anaemia or a systemic iron deficiency. Iron status should be assessed in all patients.
A full iron assessment should include serum iron, ferritin, total iron-binding capacity, and percentage transferrin saturation (TSAT), and should be measured in the early morning after an overnight fast.
If serum ferritin is ≤169 picomols/L (≤75 nanograms/mL) or TSAT is <20%, treat with oral or intravenous iron replacement (oral iron may be coformulated with ascorbic acid [vitamin C] to enhance absorption). If serum ferritin is between 169 and 225 picomols/L (75 and 100 nanograms/mL), treat with intravenous iron replacement. Serum ferritin can be falsely elevated in the presence of inflammation, hence the rationale for including TSAT in the decision to treat.
No iron treatment should be used if TSAT is >45% to minimise the risk of peripheral iron overload.
Ferritin should be rechecked after 3-4 months, and then every 3-6 months until serum ferritin is >225 picomols/L (>100 nanograms/mL). If there is no ongoing cause for iron deficiency, treatment can be stopped. It should restart if RLS worsens, unless serum ferritin is ≥674 picomols/L (≥300 nanograms/mL) (the usually accepted safe upper limit).
If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals as long as serum ferritin is <674 picomols/L (<300 nanograms/mL) and TSAT is <45%.

Consider and manage any coexisting sleep disorders.

Ask about symptoms of obstructive sleep apnoea and arrange testing for this if indicated. In some cases, sleep apnoea treatment can result in improvement in RLS symptoms. Check for and manage other causes of insomnia such as depression, anxiety, or excessive caffeine or alcohol intake.[23][26]

Check for drugs that may cause or exacerbate RLS and discontinue if possible.

Consider if antidepressants, antipsychotics, dopamine-blocking agents such as metoclopramide, or sedating antihistamines may be contributing to symptoms and discontinue them if this is feasible without causing the patient harm.[23][26]

Advise patients to implement lifestyle modifications.

Lifestyle or activity options are available, including massage, exercise, stretching, and warm baths before bedtime, although high quality evidence to support the efficacy of these is lacking.[35] Guidelines recommend mental alerting activities, such as video games or crossword puzzles, to reduce symptoms at times of boredom, as well as a trial of abstinence from caffeine and alcohol.[23]

Intermittent RLS

Intermittent RLS is defined as restless legs symptoms that are troublesome enough to require treatment but occur on average less than twice per week.

If symptoms are not frequent enough or significantly troublesome enough to warrant pharmacological treatment, lifestyle or activity options, as detailed above, should be tried initially.

If short-term pharmacological treatment is required, carbidopa/levodopa can be used on an on-demand basis for RLS that occurs intermittently in the evening, at bedtime, or on waking during the night, or for RLS associated with specific activities, such as aeroplane or lengthy car journeys, or theatre attendance.[26] An extended-release formulation can be used before bed for RLS that wakes the patient during the night.[23] Possible adverse effects with carbidopa/levodopa treatment include augmentation (drug-induced worsening of symptoms) and rebound (symptoms occurring in the late night or early morning after the drug wears off), as well as a risk of impulse control disorders. As a result, it should be prescribed for intermittent use only, without exceeding the maximum approved dose, and patients should be monitored for augmentation and impulse control disorders.[23][26] When stopping carbidopa/levodopa, patients should be gradually tapered off the drug to try and avoid rebound symptoms.[26]

A low-potency opioid or benzodiazepine receptor agonist (including benzodiazepines) may also be considered for intermittent use before sleep.[23] However, the American Academy of Sleep Medicine conditionally suggests against the use of clonazepam, but the certainty of evidence for this recommendation is very low.[26] Carbidopa/levodopa should be gradually stopped after tapering and monitoring for rebound RLS symptoms before commencing the new treatment. Prescription should be based on clinical experience, and caution used due to the potential for abuse, dependency, and adverse events.[36][37] [ ] Adverse effects of opioids include constipation and nausea. Tramadol can rarely cause seizures and is the only non-dopaminergic drug occasionally associated with the development of augmentation.[23] The American Academy of Sleep Medicine states that there is insufficient and inconclusive evidence to recommend tramadol in RLS.[26]

Benzodiazepines and benzodiazepine receptor agonists are especially useful in patients who have another cause of poor sleep in addition to RLS, such as anxiety. Short-acting agents, such as zolpidem or zaleplon, may be helpful for initiation insomnia caused by RLS, whereas intermediate-acting agents, such as temazepam, may be helpful for RLS that awakens the patient later in the night. Adverse effects include risk of falls, cognitive disturbance, sleep-walking, and sleep-eating disorders. Lower doses should be used in women and older patients. There are no adequate controlled trials of benzodiazepines in RLS and it is thought that the drugs act by treating the associated insomnia or anxiety, rather than the sensory or motor symptoms of the disorder.[23]

Chronic persistent RLS

Defined as restless legs symptoms that are frequent and troublesome enough to require daily treatment, usually occurring on average at least twice a week and resulting in moderate or severe distress.[23]

Non-pharmacological options should be instituted (as for intermittent symptoms) and iron stores evaluated (and supplemented if appropriate) in all patients.[2][23][26][28]

Gabapentinoids (e.g., pregabalin, gabapentin) are the first-line pharmacological option. They may provide extra therapeutic benefit in patients with comorbid insomnia, anxiety, or chronic pain. Treatment should commence at a low dose and be titrated every few days according to response.[23] Gabapentin enacarbil is a prodrug of gabapentin that has extended-release properties and has been shown to improve RLS symptoms compared with placebo.[2][26][38][39][40][41][42] It is approved by the US Food and Drug Administration (FDA) for the treatment of primary RLS. It may be a good option for untreated RLS that is present for much of the day and night.[23] Adverse effects of gabapentinoids include daytime drowsiness, dizziness, unsteadiness, cognitive disturbances, oedema, weight gain, depression, an increased potential for abuse in patients with a history of substance misuse disorder, and occasional respiratory depression in patients with underlying lung disease and/or untreated obstructive sleep apnoea.[23][26]

If gabapentinoids are contraindicated or not tolerated, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine) can be used as a reasonable alternative.[23] They have been shown to improve quality of life and reduce symptoms in patients with RLS.[43][44] Dopamine agonists were previously used as first-line treatment for RLS, but the high incidence of augmentation (suggested by a worsening of RLS accompanied by the need to increase the dose of dopamine agonist) and risk of developing impulse control disorders has led to a shift towards gabapentinoids being first line, and the American Academy of Sleep Medicine suggests against the standard use of these drugs.[23][26][29][45] If dopaminergic drugs are chosen as initial treatment, the daily dose should be as low as possible and not exceed the maximum approved dose for RLS.[27] Patients should be informed about the risk of augmentation associated with dopamine agonists.[26]

Augmentation is more likely with pramipexole and ropinirole, occurring in 40% to 70% of patients during a 10-year period. It is less likely with the rotigotine transdermal patch; 36% of patients will develop augmentation after 5 years while using this.[23] If augmentation occurs, the dopamine agonist can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms, with close monitoring to detect progressive augmentation. Alternatively, the patient can be switched to a rotigotine transdermal patch, with gradual tapering of the initial dopamine agonist and monitoring for rebound RLS symptoms.[26]

An opioid can be used to treat moderate to severe RLS in appropriately screened patients, and in more severe cases of augmentation.[23][26][27]

Refractory RLS

RLS is considered to be refractory if unresponsive to monotherapy with tolerable doses of a gabapentinoid or dopamine due to reduced efficacy, augmentation, or adverse effects.[23][37] Referral to an RLS specialist, if available, should be considered.

Iron status should be rechecked and iron replacement commenced if stores are low. Intravenous iron should be given if serum ferritin is between 169 and 225 picomols/L (75 and 100 nanograms/mL). If serum ferritin is ≤169 picomols/L (≤75 nanograms/mL) or TSAT is <20%, intravenous iron can be considered if symptoms remain severe after a trial of oral iron, or if the patient is intolerant of or unable to absorb oral iron, or a more rapid response is needed due to severity of symptoms.[23][26][28]

Other exacerbating factors should be screened for, including drugs that can worsen symptoms, change in lifestyle such as more sedentary behaviour or shift work, and other causes of sleep disturbance such as sleep apnoea.[23][26]

Combination therapy with drugs of different classes can be considered; a second agent is added while an attempt is made to reduce the dose of the initial drug. Second agents may include:[23]

A dopamine agonist for patients treated with a gabapentinoid.
A gabapentinoid for patients treated with a dopamine agonist.
An opioid.

Low-dose opioid monotherapy can also be considered in appropriately screened patients. Opioids are very effective in treating severe, refractory RLS, improving sleep and quality of life, and reducing daytime tiredness. When used appropriately, the need to increase the dose is uncommon, and misuse is infrequent in those with no history of substance misuse disorder. It is important to screen patients by asking about risk factors for opioid abuse, including personal and family history of substance abuse, and an opioid contract should be signed by the patient and physician.[23]

Adverse effects of opioids include nausea, constipation, urinary retention, itch, daytime drowsiness, cognitive dysfunction, falls, low testosterone, secondary adrenal insufficiency, central sleep apnoea, and a risk of respiratory depression. Close monitoring is therefore required; however, these drugs are usually well tolerated at the low recommended doses. Long-acting or extended-release preparations are recommended, as most patients switching onto opioids will have augmented symptoms present for >12 hours per day.[23][26]

Special populations

Pregnancy and lactation

Most patients can be managed with lifestyle modifications and correction of iron stores if needed.[23][46][47] Vitamin C can enhance the absorption of oral iron. However, the safety of vitamin C use during pregnancy is debated and it should therefore be avoided.[46] Non-pharmacological treatments include moderate-intensity exercise, yoga, massage, pneumatic compression devices, treatment of obstructive sleep apnoea, and avoidance of aggravating factors.[46][47]

Drug treatment should be reserved for severe RLS and should be avoided in the first trimester if possible. The lowest effective dose should be used for the shortest duration possible (and on an intermittent, rather than continuous, basis if possible). The risk-benefit ratio of drugs in pregnancy should be carefully discussed with each patient and the need for ongoing treatment periodically reassessed, particularly after iron stores are replete and at delivery.[23]

Low-dose clonazepam (a benzodiazepine) can be considered in the second and third trimesters. Concurrent use with antihistamines and anticonvulsants should be avoided. Carbidopa/levodopa is another option.[23][46][47] The alternative dopa decarboxylase inhibitor to carbidopa, benserazide, should not be used because of the risks of congenital malformations.[23]

Low-dose oxycodone before bed can be considered for severe, refractory symptoms in the second and third trimesters, but the neonate would need to be monitored for symptoms of opioid withdrawal.[23][46][47]

In people who are breastfeeding, low-dose clonazepam and gabapentin are possible options. Low-dose tramadol can be considered for severe, refractory symptoms.[23][46][47] However, note that the American Academy of Sleep Medicine states that there is insufficient and inconclusive evidence to recommend tramadol in RLS.[26] Levodopa/carbidopa and dopamine agonists should be avoided during lactation, as dopamine inhibits prolactin production.[23][46][47]

Chronic renal insufficiency

Management is similar to that in patients with normal renal function. A single controlled trial suggested that vitamin C and E supplementation may be beneficial in patients with uraemia.[48] Iron status should be checked and treated with intravenous iron or erythropoietin if indicated. Doses of some drugs may need to be adjusted as gabapentinoids and most dopamine agonists are excreted by the kidneys. Transdermal rotigotine is an exception, as it undergoes hepatic metabolism. RLS often improves or resolves after renal transplant.[23]

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