Restless Legs Syndrome

https://www1.racgp.org.au/ajgp/2023/september/restless-legs-syndrome

Definition

• Restless legs syndrome (RLS) is a sensorimotor disorder characterised by:
  • An irresistible urge to move the legs.
  • Usually associated with uncomfortable sensations such as crawling, pulling, tingling, aching or restlessness.
  • Symptoms predominantly occurring at rest and in the evening or night.
  • Temporary improvement with movement.
• It is a clinical diagnosis; there is no single confirmatory investigation.
• RLS is not considered a neurodegenerative disorder.

Essential diagnostic criteria

All five criteria should be present:

• Urge to move the legs, usually with unpleasant sensations.
• Symptoms begin or worsen during rest or inactivity.
• Symptoms improve partially or completely with movement.
• Symptoms occur predominantly in the evening or night.
• Symptoms are not better explained by another medical, neurological or behavioural condition.

Practical mnemonic: URGE

• U – Urge to move.
• R – Worse at rest.
• G – Gets better with movement.
• E – Worse in the evening or night.
• Also exclude RLS mimics.

Classification

• Intermittent RLS
  • Untreated symptoms occur less than twice weekly.
  • At least five lifetime episodes.
• Chronic persistent RLS
  • Untreated symptoms occur at least twice weekly.
  • Usually associated with clinically significant sleep disturbance or distress.
• Refractory RLS
  • Persistent symptoms despite appropriate treatment.
  • May be caused by inadequate iron replacement, incorrect diagnosis, medication adverse effects, tolerance or dopaminergic augmentation.

Associated features and risk factors

• Sleep-onset or sleep-maintenance insomnia.
• Periodic limb movements during sleep.
• Family history, particularly with younger onset.
• Pregnancy, especially during the third trimester.
• Iron deficiency, with or without anaemia.
• Chronic kidney disease and end-stage kidney disease.
• Peripheral neuropathy.
• Increasing age.
• RLS appears approximately 50% more prevalent in females; pregnancy contributes significantly to this difference.

History

Assess:

• Nature of the sensation and urge to move.
• Relationship to rest, movement and time of day.
• Frequency, duration and severity.
• Sleep disruption and daytime functional impairment.
• Symptoms involving the arms or occurring during the day.
• Family history.
• Pregnancy possibility.
• Dietary iron intake, blood loss and gastrointestinal symptoms.
• Kidney disease.
• Neuropathy symptoms.
• Alcohol, caffeine and nicotine intake.
• Shift work, insufficient sleep and untreated obstructive sleep apnoea.
• Current and recently ceased medications.

The International Restless Legs Syndrome Rating Scale may assist with baseline severity and monitoring.

Examination

• Examination is often normal in primary RLS.
• Perform targeted examination where clinically indicated:
  • Peripheral neurological examination.
  • Peripheral pulses and vascular assessment.
  • Examination for oedema or venous disease.
  • Musculoskeletal examination.
  • Assessment for parkinsonism, akathisia or other movement disorders.

Differential diagnoses

• Nocturnal leg cramps.
• Peripheral neuropathy.
• Akathisia.
• Positional discomfort.
• Arthritis or other musculoskeletal pain.
• Myalgia.
• Venous stasis or leg oedema.
• Peripheral arterial disease or claudication.
• Spasticity.
• Habitual foot tapping or anxiety-related movement.
• Medication-induced restlessness.

Periodic limb movements during sleep are supportive but are not diagnostic of RLS and are common in older people and other sleep disorders.

Exacerbating medications

Review the indication and possible alternatives for:

• Sedating antihistamines.
• Dopamine antagonists:
  • Metoclopramide.
  • Prochlorperazine.
  • Antipsychotics.
• SSRIs and SNRIs.
• Mirtazapine, which has a relatively strong association with RLS.
• Lithium in some patients.

Do not cease clinically necessary psychotropic medication abruptly. Balance RLS symptoms against the indication for treatment.

Bupropion may be less likely than some serotonergic antidepressants to exacerbate RLS, but it is not recommended as treatment for RLS.

Investigations

Initial investigations

• FBC.
• Iron studies:
  • Ferritin.
  • Serum iron.
  • Transferrin or total iron-binding capacity.
  • Transferrin saturation.
• EUC, creatinine and eGFR.
• Pregnancy testing when clinically relevant.

Iron studies should ideally be collected:

• In the morning.
• With iron-containing supplements and iron-rich foods avoided for approximately 24 hours beforehand, where practical.

Additional investigations when indicated

• HbA1c or fasting glucose.
• TSH.
• Vitamin B12 and folate.
• Liver function.
• Magnesium or other electrolytes if clinically indicated.
• Tests for inflammatory, autoimmune or other neuropathic causes based on the history.

Polysomnography

• Not routinely required to diagnose RLS.
• Consider when:
  • Obstructive sleep apnoea is suspected.
  • Another sleep disorder is possible.
  • The diagnosis remains uncertain.

Initial management

• Confirm that the diagnostic criteria are met.
• Exclude mimics.
• Identify and treat iron deficiency.
• Review exacerbating medications.
• Treat obstructive sleep apnoea and insufficient sleep.
• Reduce or avoid caffeine, alcohol and nicotine, particularly later in the day.
• Encourage:
  • Regular moderate exercise.
  • Stretching.
  • Walking during symptoms.
  • Massage.
  • Heat or cold application.
  • Good sleep routine.
  • Mentally alerting activities during prolonged inactivity.

Evidence for many non-pharmacological measures is limited, but they are low risk and may reduce symptom burden.

Iron management

• Iron treatment should be considered when:
  • Ferritin is ≤75, or
  • Transferrin saturation is <20%.
• These thresholds are specific to RLS and are higher than those generally used to diagnose systemic iron deficiency.
• If ferritin is between 75 and 100, intravenous iron may be more effective than oral iron because gastrointestinal iron absorption becomes limited.
• Oral ferrous sulfate is reasonable when iron indices and clinical circumstances are appropriate.
• Improvement may take several weeks to three months.
• Repeat iron studies and assess response after treatment.
• Investigate the underlying cause of iron deficiency rather than simply continuing replacement indefinitely.
• Intravenous ferric carboxymaltose has the strongest current trial evidence among IV preparations but should be used according to local protocols, contraindications and monitoring requirements, including the risk of hypophosphataemia.

Pharmacological treatment

Medication is generally reserved for:

• Persistent symptoms despite correction of exacerbating factors.
• Clinically significant sleep disturbance.
• Moderate-to-severe distress or functional impairment.

. Management of chronic persistent restless legs syndrome (symptoms occurring two or more times a week)
Drug	Starting daily dose	Usual daily range	Common adverse effects
Alpha-2-delta ligands (preferred first choice)
Gabapentin	300 mg	600–2400 mg	Sedation, confusion, falls, dizziness, headaches, dependence/abuse, oedema, weight gain, increased risk of suicidal thoughts, respiratory depression
Pregabalin	75 mg	75–450 mg
Dopamine agonists
Pramipexole	125 µg	250–750 µg	Nausea, vomiting, hypotension, sleepiness, impulse control disorders High rates of augmentation might limit use
Ropinirole	25 µg	50–2000 µg
Rotigotine patch	1 mg	1–3 mg
Start at lowest dose and titrate up every three to seven days as required.

Preferred treatment: alpha-2-delta ligands

• Gabapentin or pregabalin are now preferred first-line medicines for persistent clinically significant RLS.
• In Australia, use for RLS is generally off-label.
• Give approximately one to two hours before the usual onset of symptoms.
• Adjust according to renal function.
• Potential adverse effects include:
  • Dizziness.
  • Somnolence.
  • Cognitive impairment.
  • Unsteadiness and falls.
  • Peripheral oedema.
  • Weight gain.
  • Respiratory depression, particularly with opioids or other sedatives.
  • Misuse or dependence in susceptible patients.
• Use lower starting doses and cautious titration in older or frail patients.
• They may be particularly useful when RLS coexists with:
  • Insomnia.
  • Neuropathic pain.
  • Anxiety.

The 2025 AASM guideline gives strong recommendations for gabapentin and pregabalin in adults with RLS.

Dopamine agonists

Examples include:

• Pramipexole.
• Ropinirole.
• Rotigotine.

Current evidence recommends against their routine standard use, principally because of:

• Augmentation.
• Impulse-control disorders.
• Daytime sleepiness or sleep attacks.
• Postural hypotension.
• Nausea.
• Hallucinations or behavioural disturbance.

They may still be considered in carefully selected patients who:

• Cannot tolerate alpha-2-delta ligands.
• Have contraindications to preferred treatments.
• Understand and accept the long-term augmentation risk.
• Require short-term symptom control after shared decision-making.

Monitor for:

• Symptoms beginning earlier in the day.
• Increasing severity.
• Spread to the arms or trunk.
• Need for progressively earlier or higher doses.
• Gambling, compulsive shopping, binge eating or hypersexuality.

Do not stop dopamine agonists abruptly after regular use; taper gradually.

Although pramipexole remains TGA-registered and PBS-listed as a restricted benefit for primary severe RLS, PBS availability does not mean it remains the preferred first-line treatment.

Levodopa

• Not recommended for routine or chronic treatment.
• Associated with a substantial risk of:
  • Augmentation.
  • Early-morning rebound.
  • Dizziness and somnolence.
• May occasionally be considered for selected short-term situations after discussion of risks.

Benzodiazepines

• Benzodiazepines do not treat the underlying sensorimotor symptoms of RLS.
• Clonazepam is not recommended as routine RLS treatment.
• Risks include:
  • Sedation.
  • Cognitive impairment.
  • Falls.
  • Dependence.
  • Respiratory depression.
• The 2025 AASM guideline suggests against clonazepam for RLS.

Opioids

• Do not use opioids as routine first-line or routine PRN treatment for intermittent RLS.
• Low-dose opioids may have a role in:
  • Moderate-to-severe refractory RLS.
  • Severe dopaminergic augmentation.
  • Patients who have failed or cannot tolerate other treatments.
• Risks include:
  • Sedation.
  • Constipation.
  • Falls.
  • Dependence and overdose.
  • Central sleep apnoea and respiratory depression.
• Risks are increased when combined with:
  • Benzodiazepines.
  • Gabapentinoids.
  • Other sedatives.
• Specialist sleep physician or neurologist involvement is recommended before long-term opioid therapy.

Supplements

• Magnesium
  • No convincing evidence supports routine magnesium supplementation for RLS.
  • Replace only where deficiency or another clinical indication exists.
• Vitamin D
  • Association studies are inconsistent.
  • Test and replace when clinically indicated or deficient.
  • Do not routinely prescribe vitamin D solely as an RLS treatment.
• Vitamin C
  • May assist oral iron absorption in selected patients.
  • It is not an established stand-alone treatment for general RLS.
  • A specific conditional recommendation exists for vitamin C in RLS associated with end-stage kidney disease, based on limited evidence.

Pregnancy

• RLS is common during pregnancy, especially in the third trimester.
• Symptoms frequently improve after delivery.
• Prioritise:
  • Confirmation and correction of iron deficiency.
  • Sleep and lifestyle measures.
  • Review of exacerbating medications.
• Medication decisions require pregnancy-specific risk assessment and, where symptoms are severe, specialist input.

When to refer

Refer to a sleep physician or neurologist when there is:

• Diagnostic uncertainty or atypical symptoms.
• Abnormal neurological findings.
• Severe or disabling symptoms.
• Failure of iron correction and appropriately selected first-line treatment.
• Suspected augmentation.
• Requirement for dopamine agonist withdrawal.
• Consideration of opioid treatment.
• Need for specialised IV iron treatment.
• Significant pregnancy-associated RLS.
• RLS associated with end-stage kidney disease.
• Coexisting complex sleep disorder.