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Management of restless legs syndrome in primary care

Restless legs syndrome (RLS), recently renamed as Willis-Ekbom disease (WED), is a common neurological disorder characterised by an uncontrollable urge to move certain parts of the body, particularly the lower limbs

Diagnosis

  • Diagnosis of restless legs syndrome (RLS) can be made if all of the following five criteria are met (International RLS Study Group [IRLSSG] diagnostic criteria):
    • 1. a need to move the legs, usually accompanied or caused by uncomfortable, unpleasant sensations in the legs
    • symptoms are:
      • 2. exclusively present or worsen during periods of inactivity/rest
      • 3. partially or totally relieved by movement, such as walking, or stretching at least as long as the activity continues
      • 4. generally worse or exclusively occur in the evening or during the night
        • exclude mimics/differential diagnosis as the occurrence of the first four essential criteria must not be solely accounted for, as symptoms primary to another medical or a behavioural condition
  • A single standard question for rapid screening of RLS has been validated by the IRLSSG, which is: 'When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings in your legs that can be relieved by walking or movement?’. This question can be used to effectively screen large patient groups, as it had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. However, the final diagnosis should always be confirmed by matching the patient’s history and symptoms with the IRLSSG diagnostic criteria, accompanied by an exclusion of secondary conditions
  • Associated features:
    • a progressive clinical course is usual
    • adults of all ages can be affected, but the prevalence increases with age; most commonly RLS affects middle-aged individuals
    • RLS is commonly accompanied by sleep disturbances most notably insomnia
  • Differential diagnosis:
    • nocturnal leg cramps
    • volitional movements such as positional discomfort or habitual foot tapping, leg rocking
    • painful legs/moving toes syndrome
    • akathisia (hypotensive or neuroleptic induced)
    • myalgia
    • painful peripheral radiculo/neuropathy
    • vascular disease (e.g. varicose veins, venous stasis or deep vein thrombosis)
    • intermittent claudication (vascular/neurogenic)
    • arthritis
    • fibromyalgia
    • consider drug-induced RLS

Aetiology

  • The majority of cases are primary with unknown origin
  • Genetic predisposition and a chemical imbalance in the brain may play a role in over 50% patients (several genes have now been described)
  • The three major reversible secondary causes of RLS:
    • pregnancy (third trimester)
    • iron-deficiency anaemia
    • end-stage renal disease
  • Other secondary causes include:
    • vitamin B12/folate deficiency
    • peripheral neuropathy (exclude diabetes mellitus)
    • spinal disorders such as spinal nerve root irritation
    • fibromyalgia
    • rheumatoid arthritis
    • Parkinson’s disease
    • spinocerebellar ataxia, particularly SCA 3
    • Charcot-Marie-Tooth disease (type 2)

Investigations

  • Physical examination is often normal, important examinations include:
    • neurological—particularly of the peripheral nervous system
    • vascular—to exclude vascular causes
  • Required blood tests include:
    • iron studies (serum ferritin is a must)
    • full blood count (for anaemia)
    • serum vitamin B12/folate
    • serum glucose
    • urea and electrolytes
    • thyroid function tests
  • Patients with severe RLS and insomnia may require sleep studies such as polysomnography or immobilisation tests in specialised centres
  • Levodopa can be used as a clinical ‘challenge test’ for diagnosis of RLS

General principles

  • Treatment depends on the severity and frequency of symptoms
  • Severity and frequency can be determined by using the RLS severity scale
  • The international RLS rating scale is the most frequently used scale in RLS, which consists of ten questions. The answers to each question are graded into five severity categories from 0–4, with the maximum total score of 40. Scoring criteria are as follows: 1–10 (mild); 11–20 (moderate); 21–30 (severe); and 31–40 (very severe)
  • Mild RLS may be managed with reassurance and lifestyle changes
  • Severe cases may require drug therapy
  • Secondary causes and exacerbating factors should be identified and corrected:
    • iron supplementation for anaemia (low ferritin levels; ferritin needs to be rechecked after iron supplementation)
    • review concomitant treatment (RLS can be worsened by anti-depressants, calcium channel blockers, anti-nausea drugs, and some anti-allergy medications)
    • limiting other triggers (e.g. avoiding a high intake of caffeine or alcohol consumed during the evening)
    • foot care in diabetic neuropathy
  • Mineral supplementation (magnesium, potassium, and calcium) may prove useful

Non-pharmacological intervention

  • Good sleep hygiene and habits are helpful; advise patients to:
    • sleep in a quiet, comfortable, and cool environment
    • go to bed and wake at a regular hour (advise going to bed late and waking late)
    • avoid taking diuretics or caffeine before bedtime
  • During an attack, patients may find benefit from:
    • walking and stretching
    • bathing in hot or cold water
    • relaxation exercises (biofeedback or yoga)
    • distracting the mind
    • massaging affected limbs

Pharmacological treatment

  • Please see individual drug information prior to prescribing
  • Patient age should be taken into account
  • Use medication cautiously in pregnancy, RLS normally improves after parturition
  • A step-by-step approach to drug therapy may be useful
  • Start with a dopamine agonist ([DA] pramipexole, ropinirole, and rotigotine skin patch are the licensed agents) usually (but not always) administered as a single, evening dose:
    • if intolerant to one agent, try an alternative DA
    • alleviates symptoms in at least 70% of patients
  • Levodopa, taken at bedtime, may be used if patients are intolerant to DAs:
    • up to 80% of patients treated will experience augmentation or rebound; therefore long-term use is limited
    • useful for intermittent RLS and as ‘rescue’
  • Levodopa and DAs:
    • use with caution in patients with angle-closure glaucoma, a history of malignant melanoma, cardiac disease, or peptic ulcer disease
    • monitor patients for development of impulse control disorders (compulsive gambling, hypersexuality) if on DAs (particularly pramipexole or ropinirole)
  • Levodopa is associated with gastrointestinal adverse events such as anorexia, nausea, and vomiting
  • Re-introduce DAs for patients in whom symptoms persist, or begin to appear in the early morning (rebound phenomenon) or in the evening/daytime with spread to the upper limb (augmentation)
  • Anti-epileptic drugs such as carbamazepine or gabapentin may be useful for refractory cases:
    • these drugs work by inhibiting hyperactivity in the nervous system that may be related to the symptoms
    • gabapentin is particularly useful for haemodialysis patients and for cases of painful RLS
  • Severe unremitting painful RLS may require treatment with strong painkillers such as codeine, tramadol, oxycodone, or oxycodone combined with naloxone (which may confer less risk of constipation, and other opiate-related side-effects):
    • treatment with such drugs should be given under specialist guidance only
  • For patients with severe insomnia, bedtime sedatives such as clonazepam or zopliclone may be useful:
    • these drugs reduce nervous activity, and promote muscle relaxation
  • None of the drugs apart from the three DAs are licensed for use in RLS

When to refer

  • Most cases of RLS can be managed by primary care, however, referral may be considered for the following reasons:
    • diagnostic uncertainty
    • treatment failure/development of augmentation
Treatment strategies for restless legs syndrome
DrugsSpecific issuesDose range
DOPAMINERGIC: (non-ergot dopamine agonists are usually the first choice. Ergot dopamine agonists such as cabergoline are no longer recommended owing to the risk of cardiac valvulopathy)
Pramipexole Licensed for the treatment of moderate to severe RLS
Good for periodic limb movements
High rates of augmentation
0.125–0.75 mg (salt) od
Ropinirole Licensed for the treatment of moderate to severe RLS
Good for periodic limb movements
Augmentation occurs on prolonged use
0.25–4 mg od
Rotigotine (transdermal patch) Licensed for moderate to advanced RLS
Lowest augmentation rates reported so far
1–3 mg/24 hrs
Levodopa High rates of rebound/augmentation
Useful for intermittent RLS and as rescue medication for patients who need to be free of RLS symptoms for a defined period of time such as a meeting, which requires the patient to stay still
50–200 mg evening
or divided dose
OTHER DRUGS (not licensed for RLS)
Gabapentin Quick dose escalation possible
Useful second-line agent
Painful RLS
Useful in dialysis-related RLS
300–2700 mg
Carbamazepine Single/divided doses 100–600 mg
Oxycodone
or
prolonged-release
oxycodonenaloxone
Painful RLS 2.5–25 mg
5.0/2.5–40/20 mg twice daily
Tramadol Painful RLS and insomnia 50–100 mg
Clonazepam Useful for associated insomnia 0.5–2 mg evening dose
Clonidine Uraemia 0.15–0.9 mg
Iron sulphate Iron deficiency (low ferritin levels) 200 mg tid oral

full guidelines available from…
RLS-UK, PO Box 61702, London SE9 9DD; Tel - 01634 260483 (Monday 9-11am and Thursday 9-11am);
Email— helpline@rls-uk.org;www.rls-uk.org

L Klingelhoefer, A Sauerbier, P Reddy, K Ray Chaudhuri. Management of restless legs syndrome in primary care.
First included: June 2006, updated September 2014.