Restless Legs Syndrome

Restless legs syndrome (RLS) is a common sensory motor disorder characterised by an irresistible urge to move the legs. The diagnosis of RLS is clinical and based on clear diagnostic criteria. There are four primary criteria listed by the International Restless Legs Syndrome Study Group (IRLSSG) which must be present in order to support a diagnosis of RLS:

1. An urge to move the legs, usually accompanied, or caused, by uncomfortable and unpleasant sensations in the legs
2. The urge or sensations worsen during periods of rest or inactivity such as lying or sitting
3. The urge or sensations are partially or totally relieved by movement, at least for as long as the activity continues
4. The urge or sensations are worse in the evening or during the night.

Other criteria which support the diagnosis of RLS include positive family history and response to dopaminergic drug treatment or periodic limb movement. RLS is also classified as either idiopathic or secondary to several other conditions. These conditions include iron deficiency, end stage renal disease and pregnancy.

The prevalence of RLS increases with age, which may be attributed to the increase of comorbidities with age that predispose to secondary RLS. Women appear to be more susceptible to RLS, and most studies find that women are at least 50% more likely to have RLS than men.

Pharmacological Management

1. Dopaminergic agents

Levodopa

The use of levodopa, in combination with benserazide or carbidopa, is effective for infrequent and mild symptoms of RLS. The duration of action of these drug combinations are typically between two and four hours, and therefore the therapeutic effect tends to wear off early in the night. The recommended dose of levodopa is 100-200mg (with benserazide or carbidopa, 25-50mg) orally before bedtime.

About 60-70% of patients receiving levodopa with benserazide or carbidopa develop augmentation. Augmentation may manifest as: earlier onset of symptoms in the afternoon or evening, more rapid onset of symptoms following rest, increased intensity of symptoms, and may spread to different body parts. The risk factors for augmentation include doses of levodopa above 200mg per day and timing the dose too long before sleep.

Rebound is another problem for patients taking the combination of levodopa with benserazide or carbidopa. The rebound occurs when the restless legs syndrome symptoms reappear after the drug has worn off. The longer acting controlled release formulations may be effective in patients with rebound or persistent symptoms.

Pramipexole, Ropinirole, Rotigotine

These dopamine agonists are not ergot derived, and are considered as the first line treatment for moderate to severe RLS because of their relatively benign side effect profile and increasing evidence of efficacy. The recommended dosage of pramipexole is 125 micrograms orally at bedtime initially, or in divided doses for daytime symptoms, gradually increasing to a maximum 750 micrograms daily. Ropinirole is recommended to be given as 0.5mg orally daily initially, or in divided doses, gradually increasing as tolerated to a maximum of 4mg daily. Common side effects are usually mild and transient, and are limited to nausea, lightheadedness and fatigue. They typically resolve within 10-14 days. Less common side effects include nasal congestion, constipation, insomnia and leg oedema, and these usually resolve when medication is ceased.

These agents are associated with a small risk of developing impulse control disorders, such as pathological gambling, compulsive shopping, hypersexuality, and compulsive eating. Augmentation is less common with dopamine agonists (30% of patients) when compared to levodopa. Rotigotine is available as a transdermal patch that provides continuous delivery over 24 hours, and is reserved for persistent day and night symptoms of RLS. The recommended dosage of rotigotine is 2mg transdermally daily initially, and increasing as tolerated to a maximum of 4mg daily.

Bromocriptine, Cabergoline, Pergolide

Ergot derived dopamine agonists are often used “off-label” for the treatment of RLS. They have limited use as there is concern regarding their potential to cause restrictive cardiac valvulopathy. Patients should therefore undergo an echocardiograph before, and while taking, these agents.

2. Opioids

Opioids offer an effective alternative for patients in whom dopamine agonists are contraindicated, or for the management of augmentation. Oxycontin^® controlled release tablets are recommended at a dose of 10-20mg orally before bedtime. Opioid treatment may be complicated by sedation and constipation. Occasional use is preferable as they have the potential for abuse, dependency, and symptoms of withdrawal.

3. Gabapentin, Clonazepam

Gabapentin and clonazepam are the third line treatment of RLS. Gabapentin is indicated for patients whose symptoms include pain, neuropathy, or both. It may be used as a single agent, or with other treatments. Clonazepam may be used as monotherapy in patients with mild or intermittent symptoms of RLS or as a component of combination therapy in severe cases. Clonazepam’s therapeutic benefit appears to be the ability to induce and maintain sleep that allows the patient to continue to sleep despite disturbances from RLS symptoms.

Non-pharmacological Management

Sleep hygiene measures should be recommended to all patients. Patients with mild RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Cessation of medications that may exacerbate the RSL symptoms should be considered such as selective serotonin reuptake inhibitors, antipsychotics (haloperidol, olanzapine), dopamine antagonists, tricyclics antidepressants and venlafaxine.

All patients with RLS should be assessed for iron deficiency and those with serum ferritin levels less than 50microgram/L should receive iron replacement therapy.

Light exercise should be encouraged in most patients. Some patients may benefit from different physical activities before bedtime, such as a hot or cold bath, a whirlpool bath, limb massage, or vibratory or electrical stimulation of the feet and toes.

Non-pharmacological approaches to treatment should be considered initially, prior to instigating pharmacological therapies.