Restless legs syndrome

Back

1st line –

lifestyle modifications

In patients in whom symptoms are infrequent or not significantly troublesome, 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] Those with RLS that is worsened with alcohol or caffeine should minimize use of such substances. Mental alerting activities, such as video games or crossword puzzles, may be helpful.[23]

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

Other causes of sleep disturbance such as obstructive sleep apnea, depression, or anxiety should be screened for and treated if present. In some cases, sleep apnea treatment can result in improvement in RLS symptoms.[23][26]

2nd line – carbidopa/levodopa

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

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 ≤75 nanograms/mL or TSAT is <20%, treat with oral iron replacement (e.g., ferrous sulfate) or intravenous iron replacement (e.g., ferric carboxymaltose). Oral iron may be coformulated with ascorbic acid (vitamin C) to enhance absorption. If serum ferritin is between 75 and 100 nanograms/mL, treat with intravenous iron replacement.[26] 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 minimize the risk of peripheral iron overload.

Ferritin should be rechecked after 3-4 months, and then every 3-6 months until serum ferritin is >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 ≥300 nanograms/mL (the usually accepted safe upper limit).

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

2nd line –

carbidopa/levodopa

Pharmacologic treatment may be warranted on a short-term on-demand basis during episodes of symptoms that are not daily but significantly delay sleep onset.

Carbidopa/levodopa can be used for RLS that occurs intermittently in the evening, at bedtime, or on waking during the night, or if it is associated with specific activities (e.g., airplane travel, extended car journeys, or theater 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. Carbidopa/levodopa should therefore 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]

Primary options

carbidopa/levodopa: 12.5/50 mg to 50/200 mg orally (immediate-release) once daily at bedtime when required; 25/100 mg to 50/200 mg orally (extended-release) once daily when required

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Lifestyle modifications should be recommended to all patients. These include massage, exercise, stretching, and warm baths before bedtime, although high quality evidence to support their efficacy is lacking.[35] Those with RLS that is worsened with alcohol or caffeine should minimize use of such substances. Mental alerting activities, such as video games or crossword puzzles, may be helpful.[23]

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

3rd line – low-potency opioid or benzodiazepine receptor agonist

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

3rd line –

low-potency opioid or benzodiazepine receptor agonist

A low-potency opioid or benzodiazepine receptor agonist (including benzodiazepines) may be considered for intermittent use before sleep.[23] Carbidopa/levodopa should be gradually stopped after tapering and monitoring for rebound 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 nondopaminergic drug occasionally associated with the development of augmentation.[23]

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]

Primary options

codeine sulfate: 30 mg orally once daily or in divided doses initially, increase gradually according to response, maximum 180 mg/day

tramadol: 50 mg orally (immediate-release) once daily or in divided doses initially, increase gradually according to response, maximum 200 mg/day; 100 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 200 mg/day

zolpidem: 5-10 mg orally (immediate-release) once daily at bedtime when required; 6.25 to 12.5 mg orally (extended-release) once daily at bedtime when required

zaleplon: 5-20 mg orally once daily at bedtime when required

temazepam: 7.5 to 30 mg orally once daily at bedtime when required

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

intermittent RLS: pregnant

Back

1st line –

lifestyle modifications

Most patients can be managed with lifestyle modifications and correction of iron stores if needed.[23][46][47] Nonpharmacologic treatments include moderate-intensity exercise, yoga, massage, pneumatic compression devices, treatment of obstructive sleep apnea, and avoidance of aggravating factors.[46][47]

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

If serum ferritin is ≤75 nanograms/mL or TSAT is <20%, treat with oral iron replacement (e.g., ferrous sulfate) or intravenous iron replacement (e.g., ferric carboxymaltose). 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] If serum ferritin is between 75 and 100 nanograms/mL, treat with intravenous iron replacement.[26] 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 minimize the risk of peripheral iron overload.

Ferritin should be rechecked after 6-8 weeks, and then every 3-6 months until serum ferritin is >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 ≥300 nanograms/mL (the usually accepted safe upper limit).

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

chronic persistent RLS: nonpregnant

Back

1st line –

lifestyle modifications

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

2nd line – gabapentinoid

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

2nd line –

gabapentinoid

For daily symptoms that delay sleep onset and disturb the patient, daily treatment with a gabapentinoid may be appropriate.

Gabapentinoids (e.g., pregabalin, gabapentin) are the first-line pharmacologic 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, edema, 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 apnea.[23][26]

Primary options

gabapentin enacarbil: 600 mg orally (extended-release) once daily

Secondary options

gabapentin: consult specialist for guidance on dose

pregabalin: consult specialist for guidance on dose

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

3rd line – dopamine agonist

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

3rd line –

dopamine agonist

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 has led to a shift toward 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.[26][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 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 nighttime symptoms, with close monitoring to detect progressive augmentation. Alternatively, the patient can be switched to rotigotine, with gradual tapering of the initial dopamine agonist and monitoring for rebound RLS symptoms.[26]

Primary options

pramipexole: 0.125 to 0.5 mg orally once daily at night time

ropinirole: 0.25 to 4 mg orally once daily at night time

rotigotine transdermal: apply 1 mg/24 hour patch to 3 mg/24 hour patch once daily

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

4th line – opioid

Back

4th line –

opioid

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

Primary options

codeine sulfate: 30 mg orally once daily or in divided doses initially, increase gradually according to response, maximum 180 mg/day

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

chronic persistent RLS: pregnant

Back

1st line –

lifestyle modifications

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

2nd line – low-dose clonazepam

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

If serum ferritin is ≤75 nanograms/mL or TSAT is <20%, treat with oral iron replacement (e.g., ferrous sulfate) or intravenous iron replacement (e.g., ferric carboxymaltose). 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] If serum ferritin is between 75 and 100 nanograms/mL, treat with intravenous iron replacement.[26] 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 minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

2nd line –

low-dose clonazepam

Drug treatments 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.

Consult a specialist for guidance on drug selection and doses in pregnant women.

Primary options

clonazepam: consult specialist for guidance on dose

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

All patients should be advised about lifestyle modifications.[23][46][47] Nonpharmacologic treatments include moderate-intensity exercise, yoga, massage, pneumatic compression devices, treatment of obstructive sleep apnea, and avoidance of aggravating factors.[46][47]

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

2nd line – carbidopa/levodopa

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

If serum ferritin is ≤75 nanograms/mL or TSAT is <20%, treat with oral iron replacement (e.g., ferrous sulfate) or intravenous iron replacement (e.g., ferric carboxymaltose). 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] If serum ferritin is between 75 and 100 nanograms/mL, treat with intravenous iron replacement.[26] 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 minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

2nd line –

carbidopa/levodopa

If short-term pharmacologic treatment is required, carbidopa/levodopa is an alternative to clonazepam.[23][46][47] The alternative dopa decarboxylase inhibitor to carbidopa, benserazide, should not be used because of the risks of congenital malformations.[23]

Consult a specialist for guidance on drug selection and doses in pregnant women.

Primary options

carbidopa/levodopa: consult specialist for guidance on dose

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

1st line – combination drug therapy

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

If serum ferritin is ≤75 nanograms/mL or TSAT is <20%, treat with oral iron replacement (e.g., ferrous sulfate) or intravenous iron replacement (e.g., ferric carboxymaltose). 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] If serum ferritin is between 75 and 100 nanograms/mL, treat with intravenous iron replacement.[26] 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 minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

Secondary options

ferric carboxymaltose: consult specialist for guidance on dose

ONGOING

refractory RLS: nonpregnant

Back

1st line –

combination drug therapy

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: a dopamine agonist for patients treated with a gabapentinoid; a gabapentinoid for patients treated with a dopamine agonist; an opioid.[23]

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

2nd line – opioid monotherapy

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

Back

2nd line –

opioid monotherapy

Low-dose opioid monotherapy can 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 apnea, 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]

Primary options

codeine sulfate: 30 mg orally once daily or in divided doses initially, increase gradually according to response, maximum 180 mg/day

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Lifestyle modifications should be recommended to all patients. These include massage, exercise, stretching, and warm baths before bedtime, although high quality evidence to support the efficacy of these is lacking.[35] Those with RLS that is worsened with alcohol or caffeine should minimize use of such substances. Mental alerting activities, such as video games or crossword puzzles, may be helpful.[23]

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]

1st line – low-dose oxycodone

Back

Consider –

iron supplementation

Treatment recommended for SOME patients in selected patient group

No iron treatment should be used if TSAT is >45% to minimize the risk of peripheral iron overload.

If there has been an adequate response to intravenous iron but symptoms recur, repeated infusions can be given at 12-week intervals if serum ferritin is <300 nanograms/mL and TSAT is <45%.

Primary options

ferrous sulfate: 65-130 mg orally once daily or on alternate days or three times weekly

ferric carboxymaltose: consult specialist for guidance on dose

refractory RLS: pregnant

Back

1st line –

low-dose oxycodone

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]

Consult a specialist for guidance on drug selection and doses in pregnant women.

Primary options

oxycodone: consult specialist for guidance on dose

Back

Plus –

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Lifestyle modifications should be recommended to all patients. These include massage, exercise, stretching, and warm baths before bedtime, although high quality evidence to support the efficacy of these is lacking.[35] Those with RLS that is worsened with alcohol or caffeine should minimize use of such substances. Mental alerting activities, such as video games or crossword puzzles, may be helpful.[23]

Drugs that can cause or worsen RLS (e.g., antidepressants, antipsychotics, antihistamines, metoclopramide) should be stopped if possible.[23][26]