Dopamine precursors

Dopamine is a catecholamine which acts as a neurotransmitter but cannot cross the blood-brain barrier. Levodopa (L-DOPA) is a precursor to dopamine (as well as norepinephrine and epinephrine) and can cross the blood-brain barrier. Once in the brain, L-DOPA is converted by DOPA decarboxylase to dopamine which can act on the dopamine receptors to treat RLS. However, because peripheral L-DOPA is also converted to dopamine leading to adverse effects, L-DOPA is usually given with a peripheral DOPA decarboxylase inhibitor (usually carbidopa). There is a large body of evidence supporting the effectiveness of L-DOPA in RLS. One of earliest randomized trials was done in the USA and published in 1993. This study was a randomized, double-blind, placebo-controlled, cross-over design trial evaluating carbidopa/levodopa with proproxyphene and placebo. The primary outcome was PSG measurements and sleep latency tests. The researchers found that carbidopa/levodopa normalized the PLMs and improved sleep, especially in the first 3 hours of sleep (Kaplan PW et al., 1993). However, it soon became apparent that carbidopa/levodopa had a serious drawback in regards to augmentation or rebound of RLS symptoms the following morning and/ or early afternoon. In a report from 1996, Allen and colleagues prospectively evaluated 46 consecutive patients being treated with carbidopa/levodopa. They found that 82% of RLS patients and 31% of PLMS patients experienced augmentation problems and this was severe enough to lead to medication changes in 50% of the RLS patients (Allen RP, Earley CJ, 1996). Because of augmentation issues, other researchers have evaluated using sustained-release L-DOPA preparations. Trenkwalder and colleagues did an open-label extension trial of an earlier double-blinded, cross-over study evaluating standard and sustained-release L-DOPA. In this 1 year trial they found that 60% of patients discontinued therapy due to aggravating daytime symptoms (Trenkwalder C et al., 2003). In a 2006 review, Paulus & Trenkwalder examined the world literature and concluded that augmentation is a result of severely increased dopamine concentration in the CNS and that overstimulation of the D1 receptors compared to the D2 receptors in the spinal cord may cause discomfort and PLMS. Also, iron deficiency may be a significant predisposing factor for the development of augmentation. The researchers concluded that therapy with L-DOPA or dopamine agonist should endeavour to be low-dose and that iron replacement and/or opiates are the therapies of choice to use with augmentation (Paulus W & Trenkwalder C, 2006). In summary, L-DOPA is a widely available and inexpensive therapy for RLS which has been shown in numerous studies to be beneficial in improving objective PSG findings as well as subjective measures of sleep and RLS symptoms. Unfortunately, there are problems particularly linked to L-DOPA with next morning augmentation of RLS symptoms. This does impair the usefulness of L-DOPA especially when there are newer effective dopamine agonists with a better side effect profile.

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