Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome

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Less is more: pathophysiology of dopaminergic-therapyrelated augmentation in restless legs syndrome Walter Paulus, Claudia Trenkwalder Lancet Neurol 2006; 5: 878–86 Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany (W Paulus MD) and Paracelsus Elena Klinik, Centre of Parkinsonism and Movement Disorders, Kassel, Germany (C Trenkwalder MD) Correspondence to: Prof Walter Paulus, Department of Clinical Neurophysiology, University of Göttingen, Robert Koch Strasse 40, D-37075 Göttingen, Germany [email protected]

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Therapy-related augmentation of the symptoms of restless legs syndrome (RLS) is an important clinical problem reported in up to 60% of patients treated with levodopa and, to a lesser extent, with dopamine agonists. The efficacy of low-dose dopaminergic drugs for RLS has been established, but the mode of action is unknown. Here, we review the existing data and conclude that augmentation is a syndrome characterised by a severely increased dopamine concentration in the CNS; overstimulation of the dopamine D1 receptors compared with D2 receptors in the spinal cord may lead to D1-related pain and generate periodic limb movements; iron deficiency may be a main predisposing factor of augmentation, probably caused by a reduced function of the dopamine transporter; therapy with levodopa or dopamine agonists should remain at low doses and; iron supplementation and opiates are the therapy of choice to counter augmentation.

Introduction Four essential and three supportive criteria were agreed on for the diagnosis of restless legs syndrome (RLS) at an international consensus conference in 2003.1 The essential criteria were developed from the four minimum criteria published in 19952 and include an urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs; unpleasant sensations or the urge to move begin or worsen during periods of rest or inactivity; unpleasant sensations or the urge to move are partly or totally relieved by movement and unpleasant sensations or the urge to move are worse in the evening or at night compared with during the day, or only occur in the evening or night. For the first time, “response to a dopaminergic medication” was included as an associated feature in the revised version of 2003.1 In this review we focus this criterion and on augmentation as the major complications of dopaminergic therapy in RLS (panel). The term augmentation describes an increase in the severity of RLS, a time shift in the start of symptoms to earlier in the day, a shorter latency to RLS symptoms at rest, and sometimes a spreading of symptoms to other body parts, not compatible with the half-life of the drug applied.3 The term also comprises an increase in restlessness, although this aspect has not been included in the criteria so far (panel). Further research will need a more concise definition of the criteria of augmentation. Augmentation occurs in up to 60% of patients with RLS treated with levodopa4,5 and to a lesser degree with dopamine agonists.6 There is no doubt that long-term use of levodopa causes augmentation, although intensive levodopa application does improve RLS symptoms on a short time scale—closely associated with plasma concentrations of levodopa (figure 1).3 This situation is comparable with the pronociceptive consequences of prolonged morphine exposure7 or medication-overuse headache.8 Physicians not familiar with augmentation are tempted to increase levodopa to very high dosages as the

efficacy of dopaminergic treatment weakens with longterm use, thus inducing a vicious cycle. This is similar to a situation in cognitive neurobiology, where both too much and too little dopamine can impair cognition.9 The aim of this review is to draw attention to this problem and to provide a pathophysiological concept towards understanding and avoiding augmentation in the future (figure 2).

Is RLS caused by dopamine deficiency? Unlike in Parkinson’s or Segawa’s disease, a dopaminergic deficit has never been proven in patients with RLS, despite the efficacy of levodopa in treating it. As summarised in a recent review on PET and singlephoton-emission CT in RLS,10 conflicting studies with radioligands may at best be compatible with a subtle dopamine D2-receptor dysfunction in the basal ganglia. Increased D2-receptor availability was reported in patients with RLS and this was suggested to indicate either high receptor densities or low concentrations of endogenous dopamine.11 According to the researchers, both interpretations are consistent with the hypothesis of dopaminergic neurotransmission in RLS because increased receptor concentrations can be due to receptor upregulation in response to low concentrations of endogenous dopamine.11 Whether RLS is caused by a selective loss of the A11 dopaminergic cell group in a subgroup of elderly patients remains open.12 Because PET and single-photon-emission

Panel: Clinical key features of augmentation in RLS1 • Earlier onset of symptoms of at least 2 h during the day than before initiation of dopaminergic treatment • Paradoxically increased overall intensity of symptoms inducing a vicious cycle of medication dosage increase • Latency to symptoms at rest is shorter than before treatment • Symptoms extend to other body parts • Severity of symptoms requires change of treatment

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Where does levodopa exert its effect in RLS? The spinal cord is of particular interest because it is the possible origin of periodic leg movements in sleep in RLS, although supraspinal areas are involved at several stages.12 No convincing animal models for RLS are available.12,13 Studies of dopaminergic innervation and neurotransmission in pain and locomotion provide the closest approach to paraesthesias and periodic leg movement in RLS.21,22 There are no intrinsic spinal monoaminergic neurons; the dopaminergic spinal cord innervation originates supraspinally in area A11.23 A11 axons arrive in the dorsal horn and run through the intermediate zone to reach the fine granular network in the motoneuronal area.24 The ultrastructural analysis of dopaminergic innervation of the spinal cord mainly showed axodendritic contacts and fewer axosomatic ones, with synapses in the http://neurology.thelancet.com Vol 5 October 2006

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Figure 1: Time course of concentrations of levodopa in the plasma and motor activities after a single oral dose of levodopa Single oral dose of 100 mg levodopa and 25 mg benserazide given at time 0. On an acute short-term basis, symptoms and signs of augmentation closely mirror the rapid rise and fall of plasma levodopa concentration, abating 75 min after oral levodopa administration and reappearing after 3 h. Reproduced with permission from Wiley-Liss.3

ventral horn and non-synaptic (at cervical level) innervation in the dorsal horn.25 Stimulation of the hypothalamic A11 dopaminergic cell group induces antinociception in the spinal cord26 and selectively suppresses the response of projecting neurons in the dorsal horn to noxious stimuli. In a recent study, attention was focused on a possible shift of balance towards excitation by a relative dominance of serotonergic dorsal raphe neurons after compromising A11 inhibitory function.27

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CT have low-resolution images, these techniques are unable to trace the few dopaminergic cells in A11. These cells are suspected of playing an essential part in the pathophysiology of RLS because they are the only source of spinal dopaminergic neurons.13 A further argument against a major dopaminergic deficiency is the efficacy of opioids and antiepileptic drugs in RLS therapy14 and the absence of any parkinsonian signs in patients with RLS. Dopaminergic drugs must therefore improve RLS symptoms by modulating a complex neural network and not by adjusting a specific dopamine deficit. Genetic research has not yet been clear concerning the mechanisms associated with RLS. In the familial forms of RLS, three different loci but no single gene have been identified in various families.15,16 All strategies for the identification of candidate genes associated with dopaminergic neurotransmission have so far failed, apart from the discovery of a subgroup of female patients with RLS associated with the high-activity allele of the MAO-A gene.17 In addition, a parkin mutation was found in ten of 20 patients from two families with idiopathic RLS, but this was suggested to be coincidental rather than causative.18 It has been argued that RLS most probably indicates a complex familial disease rather than a single monogenetic disease. Whether or not there is a genetic predisposition to augmentation is unknown, although numerous genes spring immediately to mind. First, levodopa pharmacokinetic profile is very variable and this may partly explain the various responses to treatment. This variability may be due to genetic variants in the transmembrane transporters or metabolising enzymes of levodopa. Second, adverse effects of levodopa in Parkinson’s disease have been associated with variants of the dopamine transporter,19 and one could ask whether the same variant is associated with augmentation. Variants in the dopamine receptors—particularly functional variants in the dopamine D3 receptor20— should also be studied.

Threshold for RLS symptoms Normal range

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Figure 2: The dopamine paradox In cognitive neurobiology an inverted U-shaped function indicates the optimal range of dopamine concentration in the frontal cortex. In RLS a ‘U’-shaped function indicates the dopamine paradox: In patients who are drug-naive, a slightly lowered dopamine concentration occurs at most (left), in optimally treated patients the dopamine concentration is within the normal range and symptoms stop. In augmented patients, (right) too much dopamine causes a reoccurrence and exaggerated RLS symptomatology.

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Figure 3: Dopaminergic synapse in a healthy person and patients with RLS A normal presynaptic dopaminergic terminal releases a certain amount of dopamine (red dots). It is suggested that dopaminergic A11 neurons in RLS release slightly less dopamine when untreated. With successful levodopa substitution, normal dopamine concentration is restored. With successful agonist therapy, dopamine molecules are partially replaced by the agonist (green dots). In cases of augmentation, either too much dopamine with levodopa therapy or an increased amount of a mixture of dopamine and dopamine agonist molecules are present in the synaptic cleft.

How does levodopa exert its effect in RLS? Levodopa is the precursor of the catecholamines and thus occupies a central position in the function of these effector systems; catecholamines are the immediate product of conversion of tyrosine to levodopa by tyrosine hydroxylase.28,29 This is the rate-limiting step in dopamine production because the major negative feedback circuit targets this enzyme. The aromatic amino decarboxylase converts levodopa into dopamine before it moves into vesicles.29 These transmitter880

containing vesicles are not typically filled up to their capacity. Storage of dopamine in the vesicles can be increased when the cytosolic concentration of the precursor levodopa is raised.30,31 This levodopa precursor supplementation will, however, not change the neurons’ firing rate. Instead, after levodopa application, more dopamine is released per spike, when vesicles are being released. Accordingly, the number of dopamine molecules per vesicle released, estimated at about 3000,29 increased up to 350% after exposure to levodopa.32 Daily injection of levodopa led to a 264% increase of brain dopamine at days 2 and 3, after which it tapered to about 164% at day 16.33 Figure 3 depicts the suggested concentration of dopamine in the synaptic cleft at different treatment stages. The stimulation of A11 neurons led to the reduction of painful sensations, an antinociceptive effect that is caused by dopamine D2 stimulation.26 This effect can be blocked by dopamine D2 receptor antagonists such as sulpiride.26 By contrast, various animal studies have shown a pronociceptive effect when the dopamine D1 receptor is stimulated with D1 or D5 dopamine agonists.21 As a correlate to the restless legs, the highest dopamine concentration seems to be present in the lumbar spinal cord of the rat (figure 4). D1 or D5 versus D2, D3, or D4 receptor activation may affect glutamatergic transmission via different G-proteins.34 Application of a D1 or D5 receptor agonist also induced long-term potentiation of C-fibre evoked field potentials in the spinal dorsal horn lasting for more than 10 h. This effect was blocked by the D1 or D5 antagonist SCH23390, whereas the D2 receptor agonist quinpirole reduced C-fibre responses that lasted for 2 h.35 Such long-term effects may be triggered by phosphorylation of receptors (eg, AMPA or NMDA) relevant for neuroplastic or even excitotoxic changes in neuronal networks. Thus, D2 activation, as provided by all clinically used dopamine agonists and by levodopa, is most probably responsible for the beneficial effect of dopaminergic treatment in RLS—ie, alleviation of paraesthesias and sensory symptoms and pain in RLS. Locomotor activity and the urge to move in RLS is not affected by isolated activation of D1 receptors, whereas, activation of postsynaptic D2 receptors slightly increases locomotion.36,37,38 To promote normal locomotion, synergistic interaction between dopaminergic D1 and D236 or D1 and D3 receptors39 is needed. Concomitant and balanced stimulation of both dopamine D1 receptors and either D2 or D3 receptors is essential to produce normal locomotor stimulation. In the context of augmentation, a generalised hyperdopaminergic state and a hyperexcitability of the dopaminergic system is needed. Early flexor reflexes are reduced by levodopa, late flexor reflexes are increased, whereas opioids depress both early and late flexor reflexes.40 This indicates a theoretical basis for the clinical experience that opioids are the therapy of choice in augmentation. http://neurology.thelancet.com Vol 5 October 2006

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Figure 4: Origin of A11 neurones in the lower midbrain, projecting to the prefrontal cortex, to the temporal cortex, and to the spinal cord Superimposed are autoradiographic data of dopamine concentration in the rat spinal cord at the cervical, thoracic, and lumbar level. Note the increased dopamine receptor concentration in the lumbar cord. Reproduced with permission from Elseveier.34

D2 autoreceptor regulation Cell bodies and dendrites of dopamine neurons express D2-like dopamine autoreceptors. D2 autoreceptor activation, through small doses of dopamine or D2 receptor agonists,41 elicits hyperpolarisation by opening a potassium channel. This feedback mechanism reduces dopaminergic transmission either by reducing the firing rate42 or the concentration43 of dopamine released per spike.44 The probability of vesicular release at central synapses is very low. At most, only one vesicle is released every two to three stimuli45,46 down to one vesicle released every ten action potentials.47 Dopamine release can be regulated by D2 autoreceptors on two different time scales: a fast one, no longer than a few seconds and probably involves ion channel modulation, and a slow one, can last from minutes to hours and involves regulation of dopamine synthesis.29 Phasic or burst-induced dopamine release alternating with tonic activity has been accepted as a general feature of dopaminergic nerve cells.48 During tonic activity there is a firing rate of about 1 Hz. The dopamine that is released by single spikes is cleared from the synaptic cleft http://neurology.thelancet.com Vol 5 October 2006

before the next spike. Tonic dopamine release is less spike-dependent than phasic or burst-induced dopamine relsease, occurs extrasynaptically, and is less affected by reuptake.49 Changes in tonic concentrations of dopamine efflux occur on a much slower timescale than changes in phasic levels measured in seconds.50 Phasic or burst-induced dopamine release is spikedependent, occurs intrasynaptically, at high concentrations, and is rapidly inactivated by reuptake. During a burst, released dopamine accumulates in the extracellular space and feeds back on to D2 autoreceptors that reduce neuronal activity by membrane hyperpolarisation.51 Dopaminergic burst-induced neurotransmission is characterised by transmitter “spill-over”—ie, dopamine released by a presynaptic terminal can diffuse beyond the synaptic cleft to reach multiple postsynaptic targets, a phenomenon called “social synapse”.29 Thus, dopamine communicates via volume transmission by diffusion to target cells distant from release sites.34,52 This spillover, evoked by a burst, is probably due to dopaminetransporter saturation.53,54 Most (>95%) of the dopamine released into the synapse is taken up again into presynaptic nerve endings by dopamine transporters,55 which belong to a family of sodium and chloride-dependent carriers.56 Dopamine transporters are highly regulated proteins with a high turnover rate; in rats, dopamine transporters have a halflife of only 2 days.57 The dopamine transporter determines the spatial extent and lifetime of dopamine in the synaptic cleft.58 Intense stimulation of dopamine D2 receptors may modulate dopamine transporter expression. Intense treatment with D2 receptor agonists resulted in increased dopamine-transporter expression in the nucleus accumbens but reduced expression in the caudate and putamen.57 Complete inactivation of the dopamine transporters substantially prolongs the lifetime of extracellular dopamine by a factor of 300.59 The dopamine transporter not only controls the duration of extracellular dopamine signals but also has a critical role in the regulation of presynaptic dopamine homoeostasis.59 In this context, it would be interesting to question how common inherited variants in the gene coding for dopamine transporters modulate expression of the transporter because preliminary data indicate that variants of the dopamine transporter are associated with adverse effects of levodopa treatment.19 There may also be other mechanisms that play a part in the severe changes of the excitability state of the dopaminergic system. Relative increased excitability of dopamine D1 receptors may have a role, because dopamine D2 receptors have been reported to be downregulated after intense administration of low doses of dopamine D2 agonists.60 Treatment with D2 receptor antagonists increases the proportion of spontaneously firing dopamine transporter cells and may shift the firing pattern from single-spike discharge to burst firing.2 881

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Enlarged vesicle with levodopa therapy

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Figure 5: Proposed mechanism of augmentation Levodopa therapy increases vesicle size and this leads to intense synaptic overflow of dopamine (blue triangles), which activates both presynaptic and postsynaptic D2 receptors and postsynaptic D1 receptors. On the postsynaptic side, the dopamine D1 and D2 receptor recycling is differently affected by intensely heightened dopamine concentrations. The degradative fate of D2 receptors is determined by an interaction with G protein coupled with receptor associated sorting protein (GASP).66 As a consequence of this GASP interaction, D2 responses in the rat brain fail to resensitise after agonist treatment. This leads to a predominance of D1 receptors at the membranes surface, which are now preferentially recycled, whereas more D2 receptors are now degraded (D1 and D2 dominating pathways marked with blue arrows). The downregulated opposite D1 and D2 pathways are marked with dotted arrows.

Augmentation and dopamine-receptor stimulation In the normal dose range, dopamine largely reduces spinal-cord excitability by the mechanisms described above.61 We propose that this is also true for uncomplicated treatment of RLS by dopaminergic drugs, but no longer for the clinical disorder of augmentation. So far, there is no direct animal model for augmentation. However, these mechanisms resemble the persistent extracellular hyperdopaminergic tone in dopamine-transporter knockout mice, accompanied by hyperactivity and an impairment in spatial learning and difficulties in suppressing inappropriate responses.62 In one study, the relative shift from net inhibitory stimulation towards D1 excitatory stimulation was accomplished in D3-receptor knockout mice.63 In these mice, D1 actions were unmasked, functionally converting the modularly action of dopamine from depression to excitation. How can both sensory and motor augmentation symptoms be explained against the background of specific stimulation of the D1, D2, and D3 receptors? Initially, the typical increase in dopamine concentration, as described above may preferentially target D1 receptors with their 882

pronociceptive characteristics for a simple anatomical reason; in the spinal cord, there are 60 times more dopamine D1 receptor binding sites than D3 receptor binding sites, and this is still ten times more than D2 receptor binding sites.64 Different numbers of receptors are, however, outweighted by a complementary higher affinity for the D3 than for the D2 and D1 receptor subtypes.65 For the D3 receptors, which belong to the inhibitory D2 receptor family, highest binding densities were reported in the superficial layers of the dorsal horn at cervical and lumbar levels. Dopamine D3 agonists may also preferentially target sensory symptoms and not motor symptoms because the lowest densities of D3 sites and highest of D1 sites were detected in the ventral horn.34,64 Compensatory counter-regulation mechanisms occur when in a hyperdopaminergic state and these may affect dopamine D1 and D2 receptors differently. Dopamine D2 receptors are reduced in number, whereas D1 receptors are recycled to the plasma membrane.66 This selective sorting could possibly leave the D1 receptor signalling unopposed during succeeding dopamine exposure. Consequently, the signalling profile of a cell, synapse, or circuit that expressed both receptor subtypes http://neurology.thelancet.com Vol 5 October 2006

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Role of iron The first mention of iron having an essential role in RLS dates back to Ekbom in 1945.68 Low iron and ferritin are important in the pathophysiology of a subgroup of patients with RLS.69 The necessity of iron supplementation has been validated in many studies,70 although more evidence is still needed. Whether there is a connection between the two pathologies for RLS involving iron and dopamine still needs to be validated.70 Dopaminergic tracts seem to be consistently sensitive to regional brain iron deficiency.71 Binding of ligands to the dopamine transporter, the serotonin transporter, and the noradrenaline transporter was reduced by iron deficiency, with the degree of effect depending on the brain region.72 During iron deficiency, the density of dopamine transporters was substantially reduced in the striatum and nucleus accumbens.73 Iron deficiency notably reduced dopamine uptake into striatal synaptosomes. The molecular mechanisms behind this apparent downregulation of the expression of dopamine transprters are still unknown. There is a highly significant correlation between iron concentration and D2 receptor densities in the striatum, but not in other brain areas, leading to a selective D2 receptor loss (but not D1 receptor loss) with iron deficiency.74 However, there are no data for the spinal cord. Iron deficiency reduces dopamine-transporter function leading to increased extracellular dopamine concentration, which triggers the vicious cycle of augmentation.72 Raised concentrations of extracellular dopamine in the striatum of iron-deficient rats is most likely the result of reduced dopamine-transporter function, probably due to changes both in transporter density and functioning.73 Reduced dopamine-transporter function leads to an overflow of dopamine in the synaptic cleft, a reduced uptake of dopamine in the presynaptic neuron, and a longer and increased stimulation of the postsynaptic dopamine receptors as reported in many studies on mice deficient in dopamine transporters. http://neurology.thelancet.com Vol 5 October 2006

500 Chronic treatment group: Saline Presynaptic quinpirole dose (0·025 mg/kg) Postsynaptic quinpirole dose (0·5 mg/kg)

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would change. With regards to augmentation, the D1 receptor response may then predominate with increased dopamine tone (figure 5).66 This degradation mechanism may also be true during treatment with dopaminergic agonists, which preferentially stimulate D2 or D3 receptors and which also cause augmentation after intense therapy. In another study, D2 dopamine receptors were more susceptible to downregulation when treated with the D2 agonist quinpirole compared with D1 receptors treated with a D1 agonist.67 Furthermore, intense treatment with the D2 or D3 agonist quinpirole, in low “presynaptic” doses, did not lead to sensitisation of the locomotor response. By contrast, high “postsynaptic” doses caused increasing sensitisation after ten quinpirole doses over 30 days (figure 6).41

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Figure 6: Locomotor response to repeated injections of quinpirole The effect of chronic treatment in rats with presynaptic and postsynaptic doses of quinpirole on the development of locomotor sensitisation, measured in terms of travelled distance (ordinate). Symbols represent the mean value of the distance travelled in 90 min after the indicated number of quinpirole or saline injections. Note that only the postsynaptic dose causes locomotor sensitisation. Reproduced with permission from Elsevier.41

Dopamine-transporter malfunction may be explanation for the association between RLS and iron-induced augmentation, but other sources of interference with dopamine concentration are also possible: a decrease in iron as a cofactor of tyrosine hydrolase may reduce its activity70 and thus downregulate dopamine production. In this case, however, we would expect RLS to be a dopamine deficiency disorder, which it has been clearly proven not to be. Another possible association—in which iron insufficiency compromises dopaminergic transmission in RLS—is reduced Thy-1 in an animal model and in the substantia nigra of RLS brains.75,76 As an integral component of many types of regulated secretory vesicles, Thy-1 is iron-responsive and plays a regulatory part in the vesicular release of neurotransmitters.75 The concept proposed here requires a long-lasting disturbance of the homoeostatic mechanisms of the dopamine system. Confirmatory data on the role of ferritin and iron in more than 300 patients on levodopa and the D2 receptor agonist cabergoline have been collected (unpublished). The beneficial action of iron supplementation in the treatment of RLS has not been proven with any firm evidence. In a trial of 28 patients with RLS who had iron saturation of less than 45% intravenous iron treatment was given and a subgroup of patients responded substantially.77 In another trial, the effect of intravenous iron on the end-stage RLS symptoms of renal disease was only transient, waning 4 weeks after infusion.78 Oral iron therapy in patients independent of their ferritin levels was not effective.79 Achieving high ferritin concentrations was not in itself a 883

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guarantee of sustained improvement.80 Augmentation has never been reported in patients with Parkinson’s disease with RLS, probably due to their dopaminergic deficiency. Nevertheless, it has been claimed that associated RLS symptoms in patients with Parkinson’s disease indicates secondary symptoms connected with lower ferritin.81 The association of RLS and augmentation in patients with Parkinson’s diease needs further assessment.

Circadian influence The key symptom of augmentation with the highest sensitivity is probably the increased severity of symptoms; the symptom with the highest specificity is probably the shifting of symptoms towards daytime occurrence. Melatonin might be involved in the worsening of symptoms of RLS in the evening and during the night.82 Clear circadian gene expression has been shown in brain regions involved in motor regulation. During the day, when rats are in their resting phase, mRNA levels for tyrosine hydroxylase were upregulated in the substantia nigra and ventral tegmental area, whereas in the caudate putamen, expression of dopamine D2 receptors was lower than during the activity phase. The expression of dopamine D1 receptors remained stable over day and night.83 Data for the spinal cord are not available, but in principle differential affection of D1 versus D2 receptor regulation seems possible at the spinal level as well. Sleep deprivation, which plays a major part in severe RLS, may not only aggravate augmentation but even elicit it. Evidence for a differential effect of dopamine D1 and D2 receptors depending on the quantity of sleep came from a series of paradoxical sleep deprivation studies in rats.84 Paradoxical sleep deprivation induces several behavioural changes, mainly uncovered by an apomorphine challenge test. Apomorphine is the most potent dopamine D1 (and D2) receptor stimulating substance. If apomorphine is given after paradoxical sleep deprivation, it increases aggressive and stereotyped behaviours.84 These effects have been ascribed either to an induced subsensitivity of presynaptic dopamine receptors or to a supersensitivity of postsynaptic receptors.85,86 Unbalancing the D1 versus D3 receptor system in D3KO mice leads, with the lack of dopamine D3 receptors, to inverse circadian dopamine synthesis in the spinal cord as measured by the synthesis rate of tyrosine hydroxylase.61

Importance of dopaminergic dose in RLS therapy Not only can dopamine act at different concentrations on different receptors to exert opposing physiological actions, but strong versus weak D1 receptor activation alone can produce opposing actions.87 There is an inverted U function (bell shaped) associating cognitive performance to D1 stimulation levels.87 The locomotor 884

effects of D2-like agonists are dose dependent.41 At lower doses, activation of D2 autoreceptors reduces dopamine release, which decreases locomotor activity.88 This may well be the correlate for so far unexplained reports in studies of RLS with very low doses of dopamine agonists in the titration phase showing beneficial effects in some patients, which do not further increase or may even decline with higher doses. Dosedependent differences probably exist for clinical reasons, otherwise low levodopa doses during treatment initiation would also stimulate preferentially D1 receptors.

Conclusions Augmentation is triggered by intense dopaminergic stimulation as a result of dopaminergic therapy and a probable overstimulation of the D1 receptor compared with the D2 and D3 receptors, predominantly at the spinal level. There are several factors that increase the risk of augmentation. One is iron deficiency, which probably acts via dopamine-transport dysfunction and dopamine overstimulation. The next most important is probably sleep deprivation. It is therefore important to avoid augmentation by keeping dopaminergic doses low. In practical terms we suggest that levodopa or dopamine agonist concentrations not exceed 20% of the maximum daily dosages used in Parkinson’s disease, equivalent to about 200–300 mg. Alternative ways to produce dopamine from levodopa require distinctly higher doses in Parkinson’s disease.89 Unbalanced D1 stimulation should be stopped by dose reduction or a switch to alternative drugs as soon as augmentation starts. Iron concentrations should be measured and corrected if low. In patients with RLS, who are iron deficient, any dopaminergic therapy should be initiated cautiously or avoided. The treatment of choice is to use opioids to stop the cascade of augmentation at a spinal level; however, the evidence with opioids is weak so far, and, on augmentation, untested except for anecdotal or series reports on tramadol. Further studies are urgently needed to confirm this premise of dopaminergic overstimulation, especially as we do not know the long-term effects of dopaminergic therapy in patients with RLS with possibly increased excitatory activity of membranes and dopamine-dysfunctional synapses.

Search strategy and selection criteria References for this review were identified by searches of MEDLINE between 1980 and July 2006, for publications associated with dopamine and augmentation. Key search terms used were “restless legs syndrome”, “periodic limb movements”, “dopamine”. The final reference list was generated on originality and relevance to the topics covered in the review.

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Contributors Each author contributed equally to the literature search for this review and the writing of this review.

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Conflicts of interest WP has received honoraria for educational lectures from Boehringer Ingelheim, GlaxoSmithKline, and Pfizer. CT has received honoraria for educational lectures from Boehringer Ingelheim, GlaxoSmithKline, Schwarz Pharma, and Novartis. WP and CT have received a research grant from GlaxoSmithKline. CT is a member of advisory boards for Boehringer Ingelheim, GlaxoSmithKline, Schwarz Pharma, and Orion.

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Acknowledgments We wish to thank Professor Jürgen Brockmöller, Willhart Knepel, and Juliane Winkelmann for critical comments and helpful suggestions and Christine Crozier for improving the English.

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