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Accepted Manuscript Title: Should the Maximum Daily Dosis of Levodopa be Limited to 400 mg/die? Author: H. Baas J. Claßen M. Gerlach M. Schwarz P. Themann D. Woitalla W. Jost PII: DOI: Reference:
S2210-5336(14)00019-7 http://dx.doi.org/doi:10.1016/j.baga.2014.04.001 BAGA 123
To appear in: Received date: Accepted date:
8-4-2014 8-4-2014
Please cite this article as: Baas H, Claßen J, Gerlach M, Schwarz M, Themann P, Woitalla D, Jost W, Should the Maximum Daily Dosis of Levodopa be Limited to 400 mg/die?, Basal Ganglia (2014), http://dx.doi.org/10.1016/j.baga.2014.04.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Should the Maximum Daily Dosis of Levodopa be Limited to 400 mg/die? Baas H1, Claßen J2, Gerlach M3, Schwarz M4, Themann P5, Woitalla D6, Jost W 7
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Klinik für Neurologie, Klinikum Hanau Klinik und Poliklinik für Neurologie, Universitätsklinikum Leipzig Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg Neurologische Klinik, Klinikum Dortmund Abteilung für Neurologie, Klinik am Tharandter Wald, Halsbrücke Klinik für Neurologie, St. Josef Hospital Bochum Parkinson-Klinik Wolfach
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Introduction
Levodopa therapy still constitutes the gold standard in the treatment of motoric
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symptoms in Parkinson’s disease, undeniably possessing as it does the best ratio between symptomatic efficacy and acute tolerance, of all available substances.
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However, in the long-term course motor complications do appear, with fluctuations in movement ability and dyskinesias. In advanced cases phenomena such as on-dose
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freezing and on-dose dystonias occur, leading as a rule to a painful loss in the quality
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of life for patients. As these phenomena occur preferentially under long-term treatment with high-dose levodopa, the question has to be addressed as to whether high daily
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dosages of levodopa (DDL) should principally be avoided. This is all the more pertinent in view of the fact that effective therapeutic alternatives are available in the form of other direct dopaminergic agents such as MAO-B inhibitors und COMT inhibitors which permit a substantial reduction in the daily dosage of levodopa. For the USA, the Food and Drug Administration (FDA) has approved a
maximum daily dosage of 8 times carbidopa/levodopa 100/25 mg, while in the Federal Republic of Germany the corresponding recommendation is to avoid exceeding the daily dose of 800/200 mg for carbidopa/levodopa or levodopa/benseracid. The guidelines published in 2012 by the German Society for Neurology (Deutsche Gesellschaft für Neurologie, DGN) do not detail an explicit maximum dose, rather they recommend limiting the initial daily dosages of levodopa/decarboxylase inhibitor to within 300 and 600 mg, with higher amounts being recommended only for
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individual cases. For advanced stages of the disease no concrete recommendations are given [2].
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Risk Factors and the Emergence of Dyskinesias
Risk factors for the early development of dyskinesias have been identified in (a)
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a young age at the onset of the disease, (b) its long duration as well as (c) high daily
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doses of levodopa, especially when they have been distributed over a small number of single doses, which thus leads to pulsatile receptor stimulation.
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Some scientific evidence has accumulated to show that striatal dopamine concentrations achieve a relatively constant physiological level, but with increasing
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duration of the disease and concomitant loss of presynaptic capacity for dopamine storage, the striatum develops a pulsatile postsynaptic receptor stimulation due to the
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short plasma half-life of levodopa after oral administration and longer interdose
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intervals. After the administration of higher single doses of levodopa, simultaneous periodic and un-physiological dopamine concentrations are observed in the
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postsynaptic receptor. A subject for further discussion is the possibility that dyskinesias may be triggered forth by high levodopa concentrations in the striatum without first having been converted to dopamine [20]. Animal experimentation using the MPTP-hemi-Parkinson model have found that in spite of high DDL of up to 2000 mg/die no dyskinesias arose under the condition that levodopa is applied continuously. Further animal studies have shown that the risk for dyskinesias is significantly increased when a high total daily dosage is distributed among fewer single doses [24]. These data highlight the question as to whether high daily doses of levodopa should be principally avoided and in the long-term course can be avoided. Although empirical
studies
have
clearly
demonstrated
that
continuous
postsynaptic
dopaminergic receptor stimulation reduces the risk of motor complications, and despite long-standing use of levodopa there is still surprisingly very little valid clinical material
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on the optimum dose of levodopa throughout the different stages of the disease from controlled studies. Nonetheless: A recent publication relying on a post-hoc analysis of data from the STRIDE-PD and the ELLDOPA studies [4] postulated that daily levodopa doses of
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more than 400 mg should be principally avoided [15]. We feel it is important to critically review this statement (Tab.1) especially in light of the fact that both the studies only
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considered patients in relatively early phases of Parkinson’s disease (PD).
ELLDOPA and STRIDE Studies
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The primary variable under scrutiny in the ELLDOPA study was the influence of the timing for levodopa initiation on disease progression. No such influence could be
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found. But during the double-blind therapy phase with a variable administration of LDD (150/300/600 mg per day) a notably higher degree of motor benefit could be seen with
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a daily dose of 600 mg per day as compared to the one with 150 mg per day, while,
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however, at the same time the dyskinesia rate was greater under the higher LDD. But it should be noted that due to the very short duration of the study (merely nine months)
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the absolute number of motor complications was rather low and thus of limited reliability.
The STRIDE study was designed specifically to demonstrate that, even when
the levodopa plasma concentrations were kept uniform, the additional administration of entacapone could further reduce the dyskinesia rate. The study recruited Parkinson patients in an early stage of the disease without motor complications. The results did not corroborate the primary expectations, and in fact under the additional application of entacapone patients presented rather with a higher rate of dyskinesias [25]. A posthoc analysis of the study data, using a complex model, the risk of developing dyskinesias was compared in four sub-groups each of which had been treated with different LDD. The influence of entacapone was gauged to be at a factor of 1.3. The results of the analysis showed that the rates for dyskinesias and wearing-off were
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significantly lower when the daily levodopa dose was under 400 mg per day for the total observation period of 134 weeks [16]. Those patients who had higher LDD and the higher rate of dyskinesias and wearing-off phenomena, had already been significantly more severly diseased at the start of the study and had had higher
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UPDRS II/III scores. The dyskinesia risk was additionally influenced significantly by
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such factors as age at onset, sex and body weight.
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Data from Other Studies
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Evidence from the studies published to date on the optimum levodopa dosage in advanced stages is rather meager due to their lack of specific controls for levodopa
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titration and thus relies heavily on merely indirect data from clinical studies comparing levodopa with other dopaminergic agents and the daily levodopa doses applied in the
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studies (see Tab. 2).
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Daily Levodopa Doses in the Early Stage of the Disease
The optimal levodopa dose administered for early stages of the disease was
examined in a titration study with 361 patients and this found an optimum motor response under the administration on the average of 300 mg/die levodopa whereas increasing the dose to 600 mg/die failed to bring any additional benefit [6]. Additional valid data as to daily levodopa doses in the early stages of the disease can be found in those controlled comparative studies contrasting levodopa with dopamine agonists in which the two therapeutic agents were administered in an optimized daily dose. The REAL-PET study included 93 patients in the sub-group with levodopa as monotherapy. Within the first six months the dose was at first titrated upwards to 458 +/-163 mg L-Dopa and after two years to 560+/-180 mg levodopa [27]. After five years the levodopa required was on the average 427 +/-221 mg in
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combination with ropinirole while the group with levodopa monotherapy it was 735 +/398 mg [22]. As soon as levodopa was added, the initially significant reduction in the dyskinesia risk seen in the ropinirole monotherapy arm reached the same level that of the group given from the start only levodopa. Thus, a lasting and persistent effect for
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dyskinesia prevention failed to be observed. In a controlled study comparing pramipexole with levodopa as the initial therapy
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in early PD, after a duration of four years a mean levodopa dose of 434 +/-498 mg/die
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was being given in the pramipexole group while the dose for the patients initially treated with levodopa had reached 702 +/- 461 mg/die. At that tie the risk of
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dyskinesias was significantly lower for the pramipexole group, but this was not true for the risk of wearing-off fluctuations, and freezing phenomena appeared significantly
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more often in the pramipexole group [8]. After six years the average levodopa dose, as seen in an open post-observational follow-up period, was practically identical to the
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initial pramipexole group and to the initial levodopa group at approximately 400 mg
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(PRA 407.2 mg +/-264.3 mg IR or 364,5 +/-276,8 mg CR versus 395.4 +/-233.7mg IR and 413.5 +/-340.9 mg CR). Dyskinesias and wearing-off-fluctuations were
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significantly more frequent in the levodopa group while fatigue in the time was so in the pramipexole group. 88% of the initial pramipexole group (versus 54%) was being treated significantly more frequently with a dopamine agonist. After six years of treatment the differences in UPDRS motor-scores between the two groups did not reach significance [18].
During an open follow-up study (lasting up to six years) on rotigotine as initial monotherapy in newly diagnosed patients, it was apparent that 75% of the patients required a therapy with levodopa on the average after one year. The mean levodopa dose for the entire post-observational period reached on the average 373+/-184 mg/die per. Information as to the exact course of the dosage administered over time was not detailed [3]. Page 5 of 15
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Daily Levodopa Dosage in Advanced Stages
Data from controlled comparative clinical studies indicate that in more advanced stages of the disease LDD’s clearly over 600-700 mg often prove necessary in order to
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achieve a satisfactory clinical benefit as to motor performance. In the LARGO study (23) altogether 687 patients were already being given approximately 700 mg as their
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introductory daily dose for the beginning of the study after nine years with the disease,
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distributed over on the average 4.8 daily doses. And at the same time approximately 60% of these patients were under a combination therapy with a dopamine agonist.
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With the addition of rasagiline or entacapone the LDD could be reduced by but a slight 24 mg or 19 mg.
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Similarly, clearly higher LDD’s were given in an open follow-up study on two prior publications on rotigotine (CLEOPATRA-PD and PREFER study) after eight
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years of the disease over a post-observational period of a further four to six years (10).
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Mean LDD increased over the period of observation from an average of 990+/-630 mg/die to 1400+/-860 (!) mg/die.
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After ten years of the treatment, the average LDD in the ropinirole arm of the
REAL-PET study 631+/-260 mg and in the levodopa arm 800+/-397 mg. Parallel to these levodopa doses, 88% of the patients in the ropinirole arm had in addition a dopamine agonist as co-medication, whereas only 52% of the primary levodopa arm were changed to a combination with a dopamine agonist (7). In a further study [17] on the adjuvant administration of ropinirole LDD’s of 800 mg/die were documented at baseline for patients with an average course of the disease of just under nine years. The adjuvant administration of ropinirole prolonged release achieved a maximum average reduction of the LDD to 550 mg, but no lower than that. In far advanced stages a significant stabilisation can often be once again achieved in patients with extensive fluctuations and dyskinesias with continuous jejunal infusion of a levodopa gel (Duodopa®). In the respective studies the LDD’s that
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were administered were clearly well over 400 mg/die. At the same time, the patients recruited for these studies had already been pretreated (before being changed to continuous jejunal levodopa infusion therapy (LCIG= levodopa carbidopa intrajejunal gel) with high oral LDD’s, usually in high-dose combination withdopamine agonists
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and/or entacapone. In the study by Nyholm et al. (14), 135 patients with long-term advanced
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Parkinson’s disease were changed to LCIG, in 63% in the form of monotherapy. The
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daily LCIG dosage attained 1400 mg/die in the post-observational phase of, on the average, four years and after a mean 18 year course of the disease. An almost
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identical high level of LDD was documented in a retrospective analysis of 59 patients with an average of 13 years with Parkinson’s disease, who were treated with
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continuous enteral levodopa infusions (33). Before being changed to LCIG, the patients had been pretreated on the average with 1300 mg of oral levodopa per day.
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After changing to an LCIG, the LDD increased slightly 1450 mg per day and remained
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constant after that in the further course. A recent publication on a controlled, doubleblind study contrasting LCIG with oral levodopa in 71 patients with an average age
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since disease onset of 11 years [15], the average LDD at the start of the study in the two therapy arms was 1005 and 1130 mg/die respectively. In the further course of the study after an optimized titration a further increase of 90 mg was given for the LCIG group and one of 250 mg for the patients treated with oral levodopa. Altogether for Parkinson patients with advanced stages of the disease, there
are no data from dedicated titration studies on the optimum levodopa dosage, neither as monotherapy nor as combination therapy with other dopaminergic drugs. In spite of this situation, the daily doses published to date in comparative studies attain a level well over 800 mg/die for these patients. There are no valid data on specific aspects of the late phase in Parkinson’s such as camptocormia and the Pisa syndrome. But there is some indication from published work that dopamine agonists do constitute a risk factor for their development
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[30] and that possibly a partial improvement can after all be achieved in a selection of patients through high-dosed daily levodopa of over 1000 mg/die. In a retrospective longitudinal cohort study (1) in a total of 195 patients no safety risks were found after exceeding the FDA maximum dose of 800 mg levodopa
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per day. In comparing patients with daily doses of over and under 800 mg per day, no significant differences were found in terms of motor behavior and quality of life, but a
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significant improvement in mood and quality of life. A generalized deterioration in
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fluctuations or dyskinesia was not observed when the 800mg LTD threshold was surpassed. Altogether the study demonstrates that an additional clinical benefit can be
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achieved when an LDD of 800 mg/die is exceeded in the respective patient collective.
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Conclusions for Maximum Levodopa Dosage
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In spite of extensive clinical experience in the use of levodopa in treating
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Parkinson patients, the quality of the data from controlled studies on an optimum daily dosage is at the present not particularly exploitable or valid.
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If in particular the titration data from studies comparing dopamine agonists with
levodopa in newly diagnosed patients are taken to evaluate such a recommendation, a trend does become apparent for supporting the idea that LDD of from 300 to 400 mg/die are adequate for the initial dosaging as well as for the subsequent two to four years I the majority of cases in order to reach a satisfactory motor response. This range of the dose has been confirmed in the titration study done by Hauser et al. (6). However, over the further course of the disease, after altogether more than six to eight years the LDD’s of at most 400 mg/die, even when combined with dopamine agonists, are again in the majority of cases no longer sufficient for attaining the desired motor benefits. The available study data indicate rather that in this phase daily doses of up to 600 to 800 mg/die, and occasionally even higher, are called for. Page 8 of 15
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Still, a low dosage of levodopa does seem to reduce the risk of developing early dyskinesias in the first two to four years of the disease. After six to eight years of treatment and the concomitant necessary increase in the LDD, this benefit disappears in the majority of cases.
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A general recommendation not to exceed LDD of 400 mg is not sufficiently founded on the studies available to date. The study from Olanow et al. [16], which is
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the basis for this recommendation, should be viewed critically from a methodological
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point of view in as much as an arbitrary grouping of LDD’s was done to create identical study group sizes.
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Further factors should be considered when deciding on the choice of optimal LDD. Unfortunately one factor which is regularly given insufficient thought is the weight
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of the patients. Lighter patients consistently require essentially lower doses than heavier ones to attain a motor benefit (26).
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In the STRIDE-PD study as well, which is the main source for the
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recommendation for administering <400 mg, the dyskinesia risk was contingent on body weight: Patients weighing less than 75 kg presented with dyskinesias far more
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frequently than those over 75 kg (16). In addition, an optimized levodopa dose can be complicated
by gastrointestinal functional disturbance in Parkinson patients.
Gastroparesis is not seldom and can cause aberrant levodopa resorption that can lead to individual adaptations with occasionally essentially higher doses (28). It should be noted that higher LDD’s, especially under continuous jejunal
levodopa infusions, can induce disturbances of vitamine B12 resorption and their directly associated polyneuropathic syndromes [5,29,11,12]. Thus, monitoring the vitamine B12 levels or the prophylactic parenteral vitamine B12 substitution is recommended when the levodopa is high-dosed and jejunal infusions are done continuously. Sex-specific differences for the efficacy of levodopa should also be kept in mind. Work from a Swedish group (13) performed a country-wide study and found
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significant sex-specific differences in the levodopa doses being given them: Even with identical dyskinesia rates male patients required approximately 15% LDD. An optimum LDD makes individual factors highly relevant. Day-time fatigue or a distinct risk for psychosis often prohibit a sufficient use of dopamine agonists so that in
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such cases the dopamine substitution therapy has to be doe exclusively with levodopa (19, 32).
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In our view, therefore, the general recommendation for restricting the maximum
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LDD to 400mg a day is an oversimplification not sufficiently evidence-based and should be avoided as much as any unreflected levodopa high-dose monotherapy. One
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recommendation can still be considered properly validated: the basic principle published, among others, in the guidelines of German Society for Neurology that
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levodopa should be given as low as possible but as high as necessary and, if necessary, in combination with dopamine agonists (2). The main risk of higher dosed
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levodopa remains in the development of dyskinesias which are induced by the
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frequent peaks in levodopa concentrations in the serum. Such peaks can be avoided by fractioned or continuous levodopa administration. In order to maintain a uniform
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levodopa serum concentration, a fractionation of the LDD among several small individual doses is necessary in advanced stages of the disease. However, keeping to an altogether lower LDD raises the risk of continually low-threshold levodopa levels and long-lasting off phases.
Furthermore, it should not be forgotten that a considerble portion of the
Parkinson patients do not develop dyskinesias even with a regime of high-dosed single doses of levodopa. Clinical predictors for this phenomenon have not yet been well characterized, but several sub-groups, as far as we know now, are frequently mentioned here: Patients with later start of therapy, those with tremor dominant forms and patients with distinct axial symptoms (31).
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In light of these considerations, improved and more precise study data are necessary for finally attaining sufficiently evidence-based therapeutic stratification with adequate levodopa dosaging.
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Abstract:
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Numerous studies have shown that, among other factors, high DDL’s constitute a significant risk for the early development of dyskinesias. In a recently published post-
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hoc analysis of material from the STRIDE-PD study high LDD’s >400 mg per day were
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identified as risk factors for the development of dyskinesias and the question was presented for discussion as to whether daily doses >400 mg should therefore be
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principally avoided. The present paper reviews the consensus reached at the expert meeting from November, 2013, which critically debated on this recommendation.
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Evidence based on reliable work on the optimum levodopa dose is meager due to the
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lack of specifically controlled titration studies and is based mainly on indirect data from clinical comparative studies on levodopa vs. other dopaminergic agents: In early
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stages of the disease daily doses usually reached 400-600 mg/die, while 700-1400 mg/die were typical in advanced cases, but in all cases the variation was considerable. Seen in this light, the present authors hesitate to support the claim that LDD’s should be limited to below 400 mg/die. This claim has not yet been corroborated sufficiently.
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[26] Walker RW, Howells AR, Gray WK. The effect of levodopa dose and body weight on dyskinesia in a prevalent population of people with Parkinson's disease. Parkinsonism Relat Disord. 2011 Jan;17[1]:27-9.
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[27] Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, Brooks DJ; REAL-PET Study Group. Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol. 2003 Jul;54[1]:93-101. [28] Woitalla D, Goetze O. Treatment approaches of gastrointestinal dysfunction in Parkinson's disease, therapeutical options and future perspectives. J Neurol Sci. 2011 Nov 15;310[1-2]:152-8. Review. PubMed PMID: 21798561. [29] Wood H. Parkinson disease: Long-term levodopa exposure may increase risk of neuropathy in patients with PD. Nat Rev Neurol. 2013 Sep;9[9]:486. [30] Yoritaka A, Shimo Y, Takanashi M, Fukae J, Hatano T, Nakahara T, Miyamato N, Urabe T, Mori H, Hattori N. Motor and non-motor symptoms of 1453 patients with Parkinson's disease: prevalence and risks. Parkinsonism Relat Disord. 2013 Aug;19[8]:725-31. [31] Zhang YH, Tang BS, Song CY, Xu Q, Lou MX, Liu ZH, Yu RH, Yan XX, Guo JF. The relationship between the phenotype of Parkinson's disease and levodopa-induced dyskinesia. Neurosci Lett. 2013 Nov 27;556:109-12. [32] Zhu K, van Hilten JJ, Putter H, Marinus J. Risk factors for hallucinations in Parkinson's disease: results from a large prospective cohort study. Mov Disord. 2013 Jun;28[6]:755-62. [33] Zibetti M, Merola A, Artusi CA, Rizzi L, Angrisano S, Reggio D, De Angelis C, Rizzone M, Lopiano L. Levodopa/carbidopa intestinal gel infusion in advanced Parkinson's disease: a 7-year experience. Eur J Neurol. 2013 Dec 7
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Korrespondenzanschrift: PD Dr. Horst Baas Klinik für Neurologie Klinikum Hanau Leimenstr. 20 D-63450 Hanau Mail: [email protected]
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15 Table 1 Review of Recommendations on Mean Levodopa Daily Doses in Various Publications Type of Trial
Duration of Disease
Eggert K et al. 2012 [2]
S2-Guideline
Early phases
Recommendation for Levodopa Daily Dose 300-600 mg
Olanow WC et al. 2013 [16] Hauser RA et al. 2009 [6]
Post-hoc analysis of data from Stocchi et al.2010 (24) Retrospective Analysis of Titration Data from Fahn et al 2004
2.5 years ~6 months
max. 400 mg max. 300 mg
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Table 2 Review of Recommendations on Mean Levodopa Daily Doses in Various Publications *At the time of the end of the study
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Publication
Type of Trial
Duration of Disease *
Study Design/Medication
Levodopa Daily Doses
Early Stage of the Disease Whone AL et al. 2003 [26]
Controlled
~2-5 Years
Levodopa vs. Ropinirol
460-560 mg
Fahn S et al. 2004 [4] Holloway RG et al. 2004 [8] PSG CALM Cohort Invest. 2009 [18] Elmer et al. 2012 [3]
Controlled Controlled Open Open
~1.5 Years ~4 Years ~6 Years ~6 Years
Levodopa vs. Placebo Levodopa vs. Pramipexole Levodopa vs. Pramipexole Levodopa vs- Rotigotin
150-600 mg ~430-700 mg ~350-400 mg ~350-400 mg
Advanced Stage of the Disease Rascol O et al. 2005 [22]
Controlled
9 Years
~700 mg
Le Witt PA et al. 2013 [10] Pahwa R et al.2007
Open Controlled
12-14 Years 9 Years
Levodopa[+Dopaminagonist] +Rasagilin/Entacapon Levodopa vs. Rotigotin Levodopa vs. Ropinirol CR
Nyholm D et al. 2010 [14]
Open
18 Years
Duodopa®
~1400 mg
Zibetti M et al. 2013 [32]
Open
13 Years
Duodopa®
~1450 mg
Olanow WC et al. 2014 [15]
Controlled
11 Years
Duodopa®
~1100-1400 mg
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~1400 mg ~550-800 mg
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S2210-5336(14)00019-7 http://dx.doi.org/doi:10.1016/j.baga.2014.04.001 BAGA 123
To appear in: Received date: Accepted date:
8-4-2014 8-4-2014
Please cite this article as: Baas H, Claßen J, Gerlach M, Schwarz M, Themann P, Woitalla D, Jost W, Should the Maximum Daily Dosis of Levodopa be Limited to 400 mg/die?, Basal Ganglia (2014), http://dx.doi.org/10.1016/j.baga.2014.04.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Should the Maximum Daily Dosis of Levodopa be Limited to 400 mg/die? Baas H1, Claßen J2, Gerlach M3, Schwarz M4, Themann P5, Woitalla D6, Jost W 7
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Klinik für Neurologie, Klinikum Hanau Klinik und Poliklinik für Neurologie, Universitätsklinikum Leipzig Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg Neurologische Klinik, Klinikum Dortmund Abteilung für Neurologie, Klinik am Tharandter Wald, Halsbrücke Klinik für Neurologie, St. Josef Hospital Bochum Parkinson-Klinik Wolfach
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Introduction
Levodopa therapy still constitutes the gold standard in the treatment of motoric
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symptoms in Parkinson’s disease, undeniably possessing as it does the best ratio between symptomatic efficacy and acute tolerance, of all available substances.
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However, in the long-term course motor complications do appear, with fluctuations in movement ability and dyskinesias. In advanced cases phenomena such as on-dose
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freezing and on-dose dystonias occur, leading as a rule to a painful loss in the quality
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of life for patients. As these phenomena occur preferentially under long-term treatment with high-dose levodopa, the question has to be addressed as to whether high daily
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dosages of levodopa (DDL) should principally be avoided. This is all the more pertinent in view of the fact that effective therapeutic alternatives are available in the form of other direct dopaminergic agents such as MAO-B inhibitors und COMT inhibitors which permit a substantial reduction in the daily dosage of levodopa. For the USA, the Food and Drug Administration (FDA) has approved a
maximum daily dosage of 8 times carbidopa/levodopa 100/25 mg, while in the Federal Republic of Germany the corresponding recommendation is to avoid exceeding the daily dose of 800/200 mg for carbidopa/levodopa or levodopa/benseracid. The guidelines published in 2012 by the German Society for Neurology (Deutsche Gesellschaft für Neurologie, DGN) do not detail an explicit maximum dose, rather they recommend limiting the initial daily dosages of levodopa/decarboxylase inhibitor to within 300 and 600 mg, with higher amounts being recommended only for
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individual cases. For advanced stages of the disease no concrete recommendations are given [2].
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Risk Factors and the Emergence of Dyskinesias
Risk factors for the early development of dyskinesias have been identified in (a)
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a young age at the onset of the disease, (b) its long duration as well as (c) high daily
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doses of levodopa, especially when they have been distributed over a small number of single doses, which thus leads to pulsatile receptor stimulation.
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Some scientific evidence has accumulated to show that striatal dopamine concentrations achieve a relatively constant physiological level, but with increasing
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duration of the disease and concomitant loss of presynaptic capacity for dopamine storage, the striatum develops a pulsatile postsynaptic receptor stimulation due to the
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short plasma half-life of levodopa after oral administration and longer interdose
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intervals. After the administration of higher single doses of levodopa, simultaneous periodic and un-physiological dopamine concentrations are observed in the
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postsynaptic receptor. A subject for further discussion is the possibility that dyskinesias may be triggered forth by high levodopa concentrations in the striatum without first having been converted to dopamine [20]. Animal experimentation using the MPTP-hemi-Parkinson model have found that in spite of high DDL of up to 2000 mg/die no dyskinesias arose under the condition that levodopa is applied continuously. Further animal studies have shown that the risk for dyskinesias is significantly increased when a high total daily dosage is distributed among fewer single doses [24]. These data highlight the question as to whether high daily doses of levodopa should be principally avoided and in the long-term course can be avoided. Although empirical
studies
have
clearly
demonstrated
that
continuous
postsynaptic
dopaminergic receptor stimulation reduces the risk of motor complications, and despite long-standing use of levodopa there is still surprisingly very little valid clinical material
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on the optimum dose of levodopa throughout the different stages of the disease from controlled studies. Nonetheless: A recent publication relying on a post-hoc analysis of data from the STRIDE-PD and the ELLDOPA studies [4] postulated that daily levodopa doses of
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more than 400 mg should be principally avoided [15]. We feel it is important to critically review this statement (Tab.1) especially in light of the fact that both the studies only
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considered patients in relatively early phases of Parkinson’s disease (PD).
ELLDOPA and STRIDE Studies
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The primary variable under scrutiny in the ELLDOPA study was the influence of the timing for levodopa initiation on disease progression. No such influence could be
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found. But during the double-blind therapy phase with a variable administration of LDD (150/300/600 mg per day) a notably higher degree of motor benefit could be seen with
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a daily dose of 600 mg per day as compared to the one with 150 mg per day, while,
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however, at the same time the dyskinesia rate was greater under the higher LDD. But it should be noted that due to the very short duration of the study (merely nine months)
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the absolute number of motor complications was rather low and thus of limited reliability.
The STRIDE study was designed specifically to demonstrate that, even when
the levodopa plasma concentrations were kept uniform, the additional administration of entacapone could further reduce the dyskinesia rate. The study recruited Parkinson patients in an early stage of the disease without motor complications. The results did not corroborate the primary expectations, and in fact under the additional application of entacapone patients presented rather with a higher rate of dyskinesias [25]. A posthoc analysis of the study data, using a complex model, the risk of developing dyskinesias was compared in four sub-groups each of which had been treated with different LDD. The influence of entacapone was gauged to be at a factor of 1.3. The results of the analysis showed that the rates for dyskinesias and wearing-off were
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significantly lower when the daily levodopa dose was under 400 mg per day for the total observation period of 134 weeks [16]. Those patients who had higher LDD and the higher rate of dyskinesias and wearing-off phenomena, had already been significantly more severly diseased at the start of the study and had had higher
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UPDRS II/III scores. The dyskinesia risk was additionally influenced significantly by
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such factors as age at onset, sex and body weight.
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Data from Other Studies
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Evidence from the studies published to date on the optimum levodopa dosage in advanced stages is rather meager due to their lack of specific controls for levodopa
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titration and thus relies heavily on merely indirect data from clinical studies comparing levodopa with other dopaminergic agents and the daily levodopa doses applied in the
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studies (see Tab. 2).
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Daily Levodopa Doses in the Early Stage of the Disease
The optimal levodopa dose administered for early stages of the disease was
examined in a titration study with 361 patients and this found an optimum motor response under the administration on the average of 300 mg/die levodopa whereas increasing the dose to 600 mg/die failed to bring any additional benefit [6]. Additional valid data as to daily levodopa doses in the early stages of the disease can be found in those controlled comparative studies contrasting levodopa with dopamine agonists in which the two therapeutic agents were administered in an optimized daily dose. The REAL-PET study included 93 patients in the sub-group with levodopa as monotherapy. Within the first six months the dose was at first titrated upwards to 458 +/-163 mg L-Dopa and after two years to 560+/-180 mg levodopa [27]. After five years the levodopa required was on the average 427 +/-221 mg in
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combination with ropinirole while the group with levodopa monotherapy it was 735 +/398 mg [22]. As soon as levodopa was added, the initially significant reduction in the dyskinesia risk seen in the ropinirole monotherapy arm reached the same level that of the group given from the start only levodopa. Thus, a lasting and persistent effect for
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dyskinesia prevention failed to be observed. In a controlled study comparing pramipexole with levodopa as the initial therapy
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in early PD, after a duration of four years a mean levodopa dose of 434 +/-498 mg/die
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was being given in the pramipexole group while the dose for the patients initially treated with levodopa had reached 702 +/- 461 mg/die. At that tie the risk of
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dyskinesias was significantly lower for the pramipexole group, but this was not true for the risk of wearing-off fluctuations, and freezing phenomena appeared significantly
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more often in the pramipexole group [8]. After six years the average levodopa dose, as seen in an open post-observational follow-up period, was practically identical to the
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initial pramipexole group and to the initial levodopa group at approximately 400 mg
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(PRA 407.2 mg +/-264.3 mg IR or 364,5 +/-276,8 mg CR versus 395.4 +/-233.7mg IR and 413.5 +/-340.9 mg CR). Dyskinesias and wearing-off-fluctuations were
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significantly more frequent in the levodopa group while fatigue in the time was so in the pramipexole group. 88% of the initial pramipexole group (versus 54%) was being treated significantly more frequently with a dopamine agonist. After six years of treatment the differences in UPDRS motor-scores between the two groups did not reach significance [18].
During an open follow-up study (lasting up to six years) on rotigotine as initial monotherapy in newly diagnosed patients, it was apparent that 75% of the patients required a therapy with levodopa on the average after one year. The mean levodopa dose for the entire post-observational period reached on the average 373+/-184 mg/die per. Information as to the exact course of the dosage administered over time was not detailed [3]. Page 5 of 15
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Daily Levodopa Dosage in Advanced Stages
Data from controlled comparative clinical studies indicate that in more advanced stages of the disease LDD’s clearly over 600-700 mg often prove necessary in order to
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achieve a satisfactory clinical benefit as to motor performance. In the LARGO study (23) altogether 687 patients were already being given approximately 700 mg as their
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introductory daily dose for the beginning of the study after nine years with the disease,
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distributed over on the average 4.8 daily doses. And at the same time approximately 60% of these patients were under a combination therapy with a dopamine agonist.
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With the addition of rasagiline or entacapone the LDD could be reduced by but a slight 24 mg or 19 mg.
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Similarly, clearly higher LDD’s were given in an open follow-up study on two prior publications on rotigotine (CLEOPATRA-PD and PREFER study) after eight
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years of the disease over a post-observational period of a further four to six years (10).
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Mean LDD increased over the period of observation from an average of 990+/-630 mg/die to 1400+/-860 (!) mg/die.
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After ten years of the treatment, the average LDD in the ropinirole arm of the
REAL-PET study 631+/-260 mg and in the levodopa arm 800+/-397 mg. Parallel to these levodopa doses, 88% of the patients in the ropinirole arm had in addition a dopamine agonist as co-medication, whereas only 52% of the primary levodopa arm were changed to a combination with a dopamine agonist (7). In a further study [17] on the adjuvant administration of ropinirole LDD’s of 800 mg/die were documented at baseline for patients with an average course of the disease of just under nine years. The adjuvant administration of ropinirole prolonged release achieved a maximum average reduction of the LDD to 550 mg, but no lower than that. In far advanced stages a significant stabilisation can often be once again achieved in patients with extensive fluctuations and dyskinesias with continuous jejunal infusion of a levodopa gel (Duodopa®). In the respective studies the LDD’s that
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were administered were clearly well over 400 mg/die. At the same time, the patients recruited for these studies had already been pretreated (before being changed to continuous jejunal levodopa infusion therapy (LCIG= levodopa carbidopa intrajejunal gel) with high oral LDD’s, usually in high-dose combination withdopamine agonists
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and/or entacapone. In the study by Nyholm et al. (14), 135 patients with long-term advanced
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Parkinson’s disease were changed to LCIG, in 63% in the form of monotherapy. The
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daily LCIG dosage attained 1400 mg/die in the post-observational phase of, on the average, four years and after a mean 18 year course of the disease. An almost
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identical high level of LDD was documented in a retrospective analysis of 59 patients with an average of 13 years with Parkinson’s disease, who were treated with
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continuous enteral levodopa infusions (33). Before being changed to LCIG, the patients had been pretreated on the average with 1300 mg of oral levodopa per day.
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After changing to an LCIG, the LDD increased slightly 1450 mg per day and remained
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constant after that in the further course. A recent publication on a controlled, doubleblind study contrasting LCIG with oral levodopa in 71 patients with an average age
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since disease onset of 11 years [15], the average LDD at the start of the study in the two therapy arms was 1005 and 1130 mg/die respectively. In the further course of the study after an optimized titration a further increase of 90 mg was given for the LCIG group and one of 250 mg for the patients treated with oral levodopa. Altogether for Parkinson patients with advanced stages of the disease, there
are no data from dedicated titration studies on the optimum levodopa dosage, neither as monotherapy nor as combination therapy with other dopaminergic drugs. In spite of this situation, the daily doses published to date in comparative studies attain a level well over 800 mg/die for these patients. There are no valid data on specific aspects of the late phase in Parkinson’s such as camptocormia and the Pisa syndrome. But there is some indication from published work that dopamine agonists do constitute a risk factor for their development
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[30] and that possibly a partial improvement can after all be achieved in a selection of patients through high-dosed daily levodopa of over 1000 mg/die. In a retrospective longitudinal cohort study (1) in a total of 195 patients no safety risks were found after exceeding the FDA maximum dose of 800 mg levodopa
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per day. In comparing patients with daily doses of over and under 800 mg per day, no significant differences were found in terms of motor behavior and quality of life, but a
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significant improvement in mood and quality of life. A generalized deterioration in
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fluctuations or dyskinesia was not observed when the 800mg LTD threshold was surpassed. Altogether the study demonstrates that an additional clinical benefit can be
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achieved when an LDD of 800 mg/die is exceeded in the respective patient collective.
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Conclusions for Maximum Levodopa Dosage
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In spite of extensive clinical experience in the use of levodopa in treating
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Parkinson patients, the quality of the data from controlled studies on an optimum daily dosage is at the present not particularly exploitable or valid.
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If in particular the titration data from studies comparing dopamine agonists with
levodopa in newly diagnosed patients are taken to evaluate such a recommendation, a trend does become apparent for supporting the idea that LDD of from 300 to 400 mg/die are adequate for the initial dosaging as well as for the subsequent two to four years I the majority of cases in order to reach a satisfactory motor response. This range of the dose has been confirmed in the titration study done by Hauser et al. (6). However, over the further course of the disease, after altogether more than six to eight years the LDD’s of at most 400 mg/die, even when combined with dopamine agonists, are again in the majority of cases no longer sufficient for attaining the desired motor benefits. The available study data indicate rather that in this phase daily doses of up to 600 to 800 mg/die, and occasionally even higher, are called for. Page 8 of 15
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Still, a low dosage of levodopa does seem to reduce the risk of developing early dyskinesias in the first two to four years of the disease. After six to eight years of treatment and the concomitant necessary increase in the LDD, this benefit disappears in the majority of cases.
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A general recommendation not to exceed LDD of 400 mg is not sufficiently founded on the studies available to date. The study from Olanow et al. [16], which is
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the basis for this recommendation, should be viewed critically from a methodological
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point of view in as much as an arbitrary grouping of LDD’s was done to create identical study group sizes.
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Further factors should be considered when deciding on the choice of optimal LDD. Unfortunately one factor which is regularly given insufficient thought is the weight
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of the patients. Lighter patients consistently require essentially lower doses than heavier ones to attain a motor benefit (26).
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In the STRIDE-PD study as well, which is the main source for the
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recommendation for administering <400 mg, the dyskinesia risk was contingent on body weight: Patients weighing less than 75 kg presented with dyskinesias far more
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frequently than those over 75 kg (16). In addition, an optimized levodopa dose can be complicated
by gastrointestinal functional disturbance in Parkinson patients.
Gastroparesis is not seldom and can cause aberrant levodopa resorption that can lead to individual adaptations with occasionally essentially higher doses (28). It should be noted that higher LDD’s, especially under continuous jejunal
levodopa infusions, can induce disturbances of vitamine B12 resorption and their directly associated polyneuropathic syndromes [5,29,11,12]. Thus, monitoring the vitamine B12 levels or the prophylactic parenteral vitamine B12 substitution is recommended when the levodopa is high-dosed and jejunal infusions are done continuously. Sex-specific differences for the efficacy of levodopa should also be kept in mind. Work from a Swedish group (13) performed a country-wide study and found
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significant sex-specific differences in the levodopa doses being given them: Even with identical dyskinesia rates male patients required approximately 15% LDD. An optimum LDD makes individual factors highly relevant. Day-time fatigue or a distinct risk for psychosis often prohibit a sufficient use of dopamine agonists so that in
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such cases the dopamine substitution therapy has to be doe exclusively with levodopa (19, 32).
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In our view, therefore, the general recommendation for restricting the maximum
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LDD to 400mg a day is an oversimplification not sufficiently evidence-based and should be avoided as much as any unreflected levodopa high-dose monotherapy. One
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recommendation can still be considered properly validated: the basic principle published, among others, in the guidelines of German Society for Neurology that
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levodopa should be given as low as possible but as high as necessary and, if necessary, in combination with dopamine agonists (2). The main risk of higher dosed
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levodopa remains in the development of dyskinesias which are induced by the
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frequent peaks in levodopa concentrations in the serum. Such peaks can be avoided by fractioned or continuous levodopa administration. In order to maintain a uniform
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levodopa serum concentration, a fractionation of the LDD among several small individual doses is necessary in advanced stages of the disease. However, keeping to an altogether lower LDD raises the risk of continually low-threshold levodopa levels and long-lasting off phases.
Furthermore, it should not be forgotten that a considerble portion of the
Parkinson patients do not develop dyskinesias even with a regime of high-dosed single doses of levodopa. Clinical predictors for this phenomenon have not yet been well characterized, but several sub-groups, as far as we know now, are frequently mentioned here: Patients with later start of therapy, those with tremor dominant forms and patients with distinct axial symptoms (31).
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In light of these considerations, improved and more precise study data are necessary for finally attaining sufficiently evidence-based therapeutic stratification with adequate levodopa dosaging.
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Abstract:
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Numerous studies have shown that, among other factors, high DDL’s constitute a significant risk for the early development of dyskinesias. In a recently published post-
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hoc analysis of material from the STRIDE-PD study high LDD’s >400 mg per day were
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identified as risk factors for the development of dyskinesias and the question was presented for discussion as to whether daily doses >400 mg should therefore be
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principally avoided. The present paper reviews the consensus reached at the expert meeting from November, 2013, which critically debated on this recommendation.
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Evidence based on reliable work on the optimum levodopa dose is meager due to the
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lack of specifically controlled titration studies and is based mainly on indirect data from clinical comparative studies on levodopa vs. other dopaminergic agents: In early
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stages of the disease daily doses usually reached 400-600 mg/die, while 700-1400 mg/die were typical in advanced cases, but in all cases the variation was considerable. Seen in this light, the present authors hesitate to support the claim that LDD’s should be limited to below 400 mg/die. This claim has not yet been corroborated sufficiently.
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[11] Mancini F, Comi C, Oggioni GD, Pacchetti C, Calandrella D, Coletti Moja M, Riboldazzi G, Tunesi S, Dal Fante M, Manfredi L, Lacerenza M, Cantello R, Antonini A. Prevalence and features of peripheral neuropathy in Parkinson's disease patients under different therapeutic regimens. Parkinsonism Relat Disord. 2014 Jan;20[1]:27-31. [12] Müller T, van Laar T, Cornblath DR, Odin P, Klostermann F, Grandas FJ, Ebersbach G, Urban PP, Valldeoriola F, Antonini A. Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord. 2013 May;19[5]:501-7 ; [13] Nyholm D, Karlsson E, Lundberg M, Askmark H. Large differences in levodopa dose requirement in Parkinson's disease: men use higher doses than women. Eur J Neurol. 2010 Feb;17[2]:260-6. doi: 10.1111/j.1468-1331. [14] Nyholm D, Klangemo K, Johansson A. Levodopa/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson's disease. Eur J Neurol. 2012 Aug;19[8]:1079-85. [15] Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, Vanagunas A, Othman A, Widnall KL, Robieson W Z, Prittchett Y, Chatamra K, Benesh J, Lenz RS, Antonini A ; Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’ s disease: a randomized, contolled, double-blind, double dummy study. Lancet Neurol . 2014: 13: 141-49 [16] Olanow WC, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, Nissinen H, Leinonen M, Stocchi F; Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease [STRIDE-PD] Investigators. Factors predictive of the development of Levodopa-induced dyskinesia and wearingoff in Parkinson's disease. Mov Disord. 2013 Jul;28[8]:1064-71. [17] Pahwa R, Stacy MA, Factor SA, Lyons KE, Stocchi F, Hersh BP, Elmer LW, Truong DD, Earl NL; EASE-PD Adjunct Study Investigators. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology. 2007 Apr 3;68[14]:1108-15.
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13 [18] Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol. 2009 May;66[5]:563-70. [19] Peretz C, Chillag-Talmor O, Linn S, Gurevich T, El-Ad B, Silverman B, Friedman N, Giladi N. Parkinson's disease patients first treated at age 75 years or older: A comparative study. Parkinsonism Relat Disord. 2014 Jan;20[1]:69-74.
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Korrespondenzanschrift: PD Dr. Horst Baas Klinik für Neurologie Klinikum Hanau Leimenstr. 20 D-63450 Hanau Mail: [email protected]
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15 Table 1 Review of Recommendations on Mean Levodopa Daily Doses in Various Publications Type of Trial
Duration of Disease
Eggert K et al. 2012 [2]
S2-Guideline
Early phases
Recommendation for Levodopa Daily Dose 300-600 mg
Olanow WC et al. 2013 [16] Hauser RA et al. 2009 [6]
Post-hoc analysis of data from Stocchi et al.2010 (24) Retrospective Analysis of Titration Data from Fahn et al 2004
2.5 years ~6 months
max. 400 mg max. 300 mg
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Table 2 Review of Recommendations on Mean Levodopa Daily Doses in Various Publications *At the time of the end of the study
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Publication
Type of Trial
Duration of Disease *
Study Design/Medication
Levodopa Daily Doses
Early Stage of the Disease Whone AL et al. 2003 [26]
Controlled
~2-5 Years
Levodopa vs. Ropinirol
460-560 mg
Fahn S et al. 2004 [4] Holloway RG et al. 2004 [8] PSG CALM Cohort Invest. 2009 [18] Elmer et al. 2012 [3]
Controlled Controlled Open Open
~1.5 Years ~4 Years ~6 Years ~6 Years
Levodopa vs. Placebo Levodopa vs. Pramipexole Levodopa vs. Pramipexole Levodopa vs- Rotigotin
150-600 mg ~430-700 mg ~350-400 mg ~350-400 mg
Advanced Stage of the Disease Rascol O et al. 2005 [22]
Controlled
9 Years
~700 mg
Le Witt PA et al. 2013 [10] Pahwa R et al.2007
Open Controlled
12-14 Years 9 Years
Levodopa[+Dopaminagonist] +Rasagilin/Entacapon Levodopa vs. Rotigotin Levodopa vs. Ropinirol CR
Nyholm D et al. 2010 [14]
Open
18 Years
Duodopa®
~1400 mg
Zibetti M et al. 2013 [32]
Open
13 Years
Duodopa®
~1450 mg
Olanow WC et al. 2014 [15]
Controlled
11 Years
Duodopa®
~1100-1400 mg
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Publication
~1400 mg ~550-800 mg
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