Approach

Treatment of primary 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][27][33]

  • 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 anemia 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 ≤75 nanograms/mL and TSAT is <45%, treat with oral iron replacement and 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 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).

  • Consider intravenous iron if moderate to severe chronic persistent or severe refractory RLS is present and ferritin is <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 as long as serum ferritin is <300 nanograms/mL and TSAT is <45%.

Consider and manage any coexisting sleep disorders.

  • Ask about symptoms of obstructive sleep apnea and arrange testing for this if indicated. In some cases, sleep apnea 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]

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

  • Consider if antidepressants, neuroleptics, 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]

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.[34] 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 pharmacologic treatment, lifestyle or activity options, as detailed above, should be tried initially.

If pharmacologic 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 airplane or lengthy car journeys, or theater 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 (drug-induced worsening of symptoms) and rebound (symptoms occurring in the late night or early morning after the drug wears off). As a result, it should be prescribed for intermittent use only.[23]

A low-potency opioid or benzodiazepine receptor agonist (including benzodiazepines) may also be considered for intermittent use before sleep.[23][35]​​​ Carbidopa/levodopa should be 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] [ Cochrane Clinical Answers logo ] 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]

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]

Nonpharmacologic options should be instituted (as for intermittent symptoms) and iron stores evaluated (and supplemented if appropriate) in all patients.[2][23]​​[27]

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][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, 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.[23]

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 toward 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 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 nighttime symptoms, with close monitoring to detect progressive augmentation. Alternatively, the patient can be switched to a gabapentinoid or rotigotine transdermal patch.

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

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 can be considered if serum ferritin is <100 nanograms/mL and 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][27]

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

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

  • A benzodiazepine (particularly if insomnia is a predominant symptom)

  • A low- or high-potency 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, and central sleep apnea. Close monitoring is therefore required; however, these medications 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]

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] Nonpharmacologic treatments include moderate-intensity exercise, yoga, massage, pneumatic compression devices, treatment of obstructive sleep apnea, and avoidance of aggravating factors.[46][47]

Medications 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. 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 breast-feeding, low-dose clonazepam and gabapentin are possible options. Low-dose tramadol can be considered for severe, refractory symptoms.[23][46][47] 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 uremia.[48] Iron status should be checked and treated with intravenous iron or erythropoietin if indicated. Medication doses 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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