Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

intermittent RLS: non-pregnant

1st line – lifestyle modifications

Back
ACUTE
|
intermittent RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
intermittent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to enhance absorption. 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).

Primary options

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

More

2nd line – carbidopa/levodopa

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ACUTE
|
intermittent RLS: non-pregnant
2nd line – 

carbidopa/levodopa

Pharmacological treatment may be warranted on an 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., aeroplane travel, extended car journeys, or theatre attendance). An extended-release formulation can be used before bed for RLS that wakes the patient during the night.[23]

Problems with carbidopa/levodopa treatment include augmentation (worsening of symptoms early in the day) and rebound (symptoms occurring in the late night or early morning after the drug wears off). Carbidopa/levodopa should therefore be prescribed for intermittent use only.[23]

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

Plus – lifestyle modifications

Back
ACUTE
|
intermittent RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
intermittent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to enhance absorption. 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).

Primary options

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

More

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

Back
ACUTE
|
intermittent RLS: non-pregnant
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][35] Carbidopa/levodopa is stopped before commencing the new medication. 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]

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

OR

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

OR

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

More

OR

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

OR

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

Plus – lifestyle modifications

Back
ACUTE
|
intermittent RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
intermittent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to enhance absorption. 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).

Primary options

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

More

intermittent RLS: pregnant

1st line – lifestyle modifications

Back
ACUTE
|
intermittent RLS: pregnant
1st line – 

lifestyle modifications

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

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

Consider – iron supplementation

Back
ACUTE
|
intermittent RLS: pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. 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] 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 6-8 weeks, 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).

Primary options

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

More

chronic persistent RLS: non-pregnant

1st line – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: non-pregnant
1st line – 

lifestyle modifications

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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to aid absorption. 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

2nd line – gabapentinoid

Back
ACUTE
|
chronic persistent RLS: non-pregnant
2nd line – 

gabapentinoid

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

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][35][38][39][40][41][42] It is approved by the Food and Drug Administration (FDA) for the treatment of primary RLS. Most people will not require it, but 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.[23]

Primary options

gabapentin: consult specialist for guidance on dose

OR

pregabalin: consult specialist for guidance on dose

OR

gabapentin enacarbil: 600 mg orally (extended-release) once daily at approximately 5 p.m.

Plus – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to aid absorption. 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

3rd line – dopamine agonist

Back
ACUTE
|
chronic persistent RLS: non-pregnant
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 towards gabapentinoids being first line.[23][28][45] If dopaminergic drugs are chosen as initial treatment, the daily dose should be as low as possible and not exceed that recommended for RLS.[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 night-time symptoms, with close monitoring to detect progressive augmentation.

Alternatively, the patient can be switched to a gabapentinoid or rotigotine. An opioid can be used in more severe cases of augmentation.[23][26]

Primary options

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

OR

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

OR

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

Plus – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to aid absorption. 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

4th line – opioid

Back
ACUTE
|
chronic persistent RLS: non-pregnant
4th line – 

opioid

An opioid can be used in more severe cases of dopamine agonist-induced augmentation.[23][26]

Primary options

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

OR

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

Plus – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to aid absorption. 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

chronic persistent RLS: pregnant

1st line – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: pregnant
1st line – 

lifestyle modifications

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

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. 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] 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

2nd line – low-dose clonazepam

Back
ACUTE
|
chronic persistent RLS: pregnant
2nd line – 

low-dose clonazepam

Medicines 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 medication 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

Plus – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: pregnant
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

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

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. 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] 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

2nd line – carbidopa/levodopa

Back
ACUTE
|
chronic persistent RLS: pregnant
2nd line – 

carbidopa/levodopa

Medicines 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 medication periodically reassessed, particularly after iron stores are replete and at delivery.[23]

If pharmacological 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

Plus – lifestyle modifications

Back
ACUTE
|
chronic persistent RLS: pregnant
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

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

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

Consider – iron supplementation

Back
ACUTE
|
chronic persistent RLS: pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. 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] 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

ONGOING

refractory RLS: non-pregnant

1st line – combination drug therapy

Back
ONGOING
|
refractory RLS: non-pregnant
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; a benzodiazepine (particularly if insomnia is a predominant symptom); a low- or high-potency opioid.[23]

See sections above for drug options and doses.

Plus – lifestyle modifications

Back
ONGOING
|
refractory RLS: non-pregnant
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ONGOING
|
refractory RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to aid absorption. 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

2nd line – opioid monotherapy

Back
ONGOING
|
refractory RLS: non-pregnant
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, and central sleep apnoea. Close monitoring is therefore required; however, these medicines 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]

Primary options

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

OR

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

Plus – lifestyle modifications

Back
ONGOING
|
refractory RLS: non-pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ONGOING
|
refractory RLS: non-pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. This should be given in combination with vitamin C to aid absorption. 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

refractory RLS: pregnant

1st line – low-dose oxycodone

Back
ONGOING
|
refractory RLS: pregnant
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

Plus – lifestyle modifications

Back
ONGOING
|
refractory RLS: pregnant
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.[34] Those with RLS that is worsened with alcohol or caffeine should minimise 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, neuroleptics, antihistamines, metoclopramide) should be stopped if possible.[23]

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

Consider – iron supplementation

Back
ONGOING
|
refractory RLS: pregnant
Consider – 

iron supplementation

Additional 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 ≤169 picomols/L (≤75 nanograms/mL) and TSAT is <45%, treat with oral iron replacement. 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] 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).

Consider intravenous iron (e.g., ferric carboxymaltose) if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <225 picomols/L (<100 nanograms/mL) and TSAT <45% and any of the following are present: oral iron treatment failure (intolerance or lack of efficacy despite a 3-month trial); a condition that blocks oral iron absorption or makes response unlikely (e.g., bariatric surgery, malabsorption syndrome, inflammatory bowel disease, or heavy uterine bleeding); contraindication to oral iron; clinical need for a more rapid response than with oral iron.

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 <674 picomols/L (<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

More

Secondary options

ferric carboxymaltose: <50 kg body weight: 15 mg/kg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course; ≥50 kg body weight: 750 mg intravenously for 2 doses (given 7 days apart), maximum 1500 mg/treatment course

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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