Treatment of Restless Legs Syndrome

Abstract

Restless legs syndrome (RLS) is a common disorder diagnosed by the clinical characteristics of restlessness in the legs associated often with abnormal sensations that start at rest and are improved by activity, occurring with a diurnal pattern of worsened symptoms at night and improvement in the morning. RLS is the cause of impaired quality of life in those more severely afflicted. Treatment of RLS has undergone considerable change over the last few years. Several classes of medications have demonstrated efficacy, including the dopaminergic agents and the alpha-2-delta ligands. Levodopa was the first dopaminergic agent found to be successful. However, chronic use of levodopa is frequently associated with augmentation that is defined as an earlier occurrence of symptoms frequently associated with worsening severity and sometimes spread to other body areas. The direct dopamine agonists, including ropinirole, pramipexole, and rotigotine patch, are also effective, although side effects, including daytime sleepiness, impulse control disorders, and augmentation, may limit usefulness. The alpha-2-delta ligands, including gabapentin, gabapentin enacarbil, and pregabalin, are effective for RLS without known occurrence of augmentation or impulse control disorders, although sedation and dizziness can occur. Other agents, including the opioids and clonazepam do not have sufficient evidence to recommend them as treatment for RLS, although in an individual patient, they may provide benefit.

Oxycodone/Naloxone PR: A Review in Severe Refractory Restless Legs Syndrome

“…The first such agent shown to be successful in the treatment of RLS was levodopa [12]; this dopamine precursor is still used occasionally in some European countries, namely Germany, Austria and Switzerland, mainly for the on-demand treatment of intermittent (as opposed to daily) RLS symptoms [9]. Although initially effective, the usefulness of dopaminergic agents may be limited by subsequent loss of efficacy (tolerance) and adverse events, including daytime sleepiness, impulse control disorders and the development of augmentation [13].…”

“…Although initially effective, the usefulness of dopaminergic agents may be limited by subsequent loss of efficacy (tolerance) and adverse events, including daytime sleepiness, impulse control disorders and the development of augmentation [13]. The latter, which is characterized by an overall worsening in RLS symptom severity compared with the pretreatment level, represents the most important long-term complication of dopaminergic treatment [9,12]. Although augmentation is most common during long-term treatment with levodopa (up to 60 % of patients), it is still a frequent occurrence during long-term treatment with NEDAs (up to 40 % of patients) [10,12].…”

“…Pregabalin appears to have a low(er) risk of augmentation relative to dopaminergic agents [15]; however, like gabapentin enacarbil and gabapentin, it is associated with sleepiness and dizziness [9,12]. Moreover, the use of a2d ligands is 'off-label', as they have yet to be approved for the treatment of RLS in Europe [8].…”

Restless Leg Syndrome in Neurologic and Medical Disorders

“…88 In addition, symptomatic relief may be achieved with antiepileptic agents, opioids, and benzodiazepines. [89][90][91] Augmentation of RLS by dopaminergic and other agents 63-65 occurs usually after prolonged administration, 89 suggesting that pathogenic imbalance persists in new steady state activities of these neurotransmitters. Muscle quietness is similarly disturbed either by administration or withdrawal of antidopaminergic, antihistaminic, antidepressant, antipsychotic, and anticonvulsant agents, consistent with the concept that oscillations in neuromodulation are in fact involved in the mechanism of RLS.…”

Editorial: Neurotherapeutics of Movement Disorders

“…While no phase III trials have been completed, Cloud et al [15] present data on therapy with a focus on those drugs with evidence from phase II double-blind trials, such as tetrabenazine, amantadine, levetiracetam, clonazepam, and gingko biloba. Comella [16] presents the current status of restless leg syndrome and the evidence for dopaminergic agents and the alpha-2-delta ligands, as well as other older medications, such as opiates and benzodiazepines. Myoclonus therapy, as reviewed by Caviness [17], should be guided by neurophysiologic classification.…”