Restless Legs Syndrome

Dopaminergic Agents

Dopaminergic agents are first-line therapy in the treatment of moderate to severe RLS and are also effective in the treatment of mild or intermittent RLS that is not responsive to nonpharmacologic intervention (Table 8).

Table 8

Dopaminergic Agents
Drug	Typical starting dose, mg	Usual therapeutic range, mg	Peak concentration, h	Half-life, h	Side effects
Dopamine receptor agonists
Nonergot dopamine receptor agonists					Mild N/V; sedation; orthostatic hypotension;
Pramipexole	0.125	0.125-0.5	2	8-12
Ropinirole	0.25	0.25-4.0	1-2	6
Dopamine precursor					Augmentation; N/V; headache
Carbidopa-levodopa	12.5/50	12.5/50-75/300	.5	1.5-2.0
Carbidopa-levodopa CR	25/100	25/100-100/400	2	3-8

N/V refers to nausea and vomiting; CR, continuous release

Augmentation
The most commonly encountered complication of long-term therapy of RLS is that of augmentation.180,181 Augmentation occurs in temporal relationship to the ingestion of medications to treat RLS—primarily dopaminergic drugs, but case reports have indicated that augmentation may occur with the use of tramadol.145,181-185 Augmentation has been shown to be most common with the use of levodopa-carbidopa186-188 and, to a lesser extent, with the use dopamine receptor agonists170,189,190; and is more likely to occur in patients with low serum ferritin levels.183

When augmentation develops, the symptoms of RLS occur at a time at least two hours before they occurred before the initiation of drug therapy. The symptoms frequently intensify and spread to previously noninvolved parts of the body (particularly the arms). In addition, the time from onset of quiescence to onset of symptoms is typically shortened.119 The rate of augmentation is highest with the use of levodopa; therefore, dopamine receptor agonists are the preferred drug for the treatment of RLS that occurs on a daily basis.

Key Features of Augmentation
Temporal relationship exists between
↑ daily medication	↑ symptom intensity
↓ daily medication	↓ symptom intensity
Sensations spread to previously uninvolved parts of the body.
The duration of treatment effect is shorter than the duration with initial therapeutic response.
Periodic limb movements while awake either occur for the first time or are worse than with initial therapeutic response or before treatment was instituted.

Augmentation should be discussed with all patients treated with dopaminergic agents; patients should be cautioned that if augmentation occurs, they should not increase their dosage of medication but, instead, should return to the prescribing physician for consultation. The treatment of augmentation may involve adjusting the timing or the dose of the medication or switching to another agent.