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 effic… Show more
“…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].…”
Section: Introductionmentioning
confidence: 99%
“…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].…”
Section: Introductionmentioning
confidence: 99%
“…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].…”
An oral, fixed-dose combination of prolonged-release (PR) oxycodone with PR naloxone (Targin(®), Targiniq(®), Targinact(®); hereafter referred to as oxycodone/naloxone PR) is approved in Europe for the second-line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome (RLS), after failure of dopaminergic therapy. Coadministration of naloxone represents a targeted approach to counteracting opioid-induced bowel dysfunction without compromising therapeutic efficacy; because of its very low oral bioavailability, naloxone blocks the action of oxycodone at opioid receptors locally in the gut. The efficacy of oxycodone/naloxone PR in patients with severe RLS inadequately controlled by previous (mainly dopaminergic) treatment has been demonstrated in RELOXYN, a 12-week, randomized, double-blind study with a 40-week open-label extension. In this pivotal study, oxycodone/naloxone PR significantly improved RLS symptoms compared with placebo from week 2 onwards; a beneficial effect of oxycodone/naloxone PR was maintained through 1 year of treatment. Furthermore, improvements in RLS symptoms in oxycodone/naloxone PR recipients were accompanied by similarly sustained improvements in disease-specific quality of life and subjective sleep variables. Oxycodone/naloxone PR was generally well tolerated, with a treatment-related adverse event profile (e.g. gastrointestinal disorders, CNS disorders, fatigue and pruritus) that was consistent with that expected for opioid therapy. Notably, there were no confirmed cases of augmentation among oxycodone/naloxone PR recipients throughout the course of the study. Results from the well-designed RELOXYN trial have thus demonstrated the value of oxycodone/naloxone PR as a second-line therapy for severe refractory RLS; further investigation of this combination product as a first-line treatment for severe RLS is now warranted.
“…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].…”
Section: Introductionmentioning
confidence: 99%
“…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].…”
Section: Introductionmentioning
confidence: 99%
“…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].…”
An oral, fixed-dose combination of prolonged-release (PR) oxycodone with PR naloxone (Targin(®), Targiniq(®), Targinact(®); hereafter referred to as oxycodone/naloxone PR) is approved in Europe for the second-line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome (RLS), after failure of dopaminergic therapy. Coadministration of naloxone represents a targeted approach to counteracting opioid-induced bowel dysfunction without compromising therapeutic efficacy; because of its very low oral bioavailability, naloxone blocks the action of oxycodone at opioid receptors locally in the gut. The efficacy of oxycodone/naloxone PR in patients with severe RLS inadequately controlled by previous (mainly dopaminergic) treatment has been demonstrated in RELOXYN, a 12-week, randomized, double-blind study with a 40-week open-label extension. In this pivotal study, oxycodone/naloxone PR significantly improved RLS symptoms compared with placebo from week 2 onwards; a beneficial effect of oxycodone/naloxone PR was maintained through 1 year of treatment. Furthermore, improvements in RLS symptoms in oxycodone/naloxone PR recipients were accompanied by similarly sustained improvements in disease-specific quality of life and subjective sleep variables. Oxycodone/naloxone PR was generally well tolerated, with a treatment-related adverse event profile (e.g. gastrointestinal disorders, CNS disorders, fatigue and pruritus) that was consistent with that expected for opioid therapy. Notably, there were no confirmed cases of augmentation among oxycodone/naloxone PR recipients throughout the course of the study. Results from the well-designed RELOXYN trial have thus demonstrated the value of oxycodone/naloxone PR as a second-line therapy for severe refractory RLS; further investigation of this combination product as a first-line treatment for severe RLS is now warranted.
“…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.…”
Section: Interpretation Of the Proposed Mechanismmentioning
“…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.…”
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