The effect of continuous levodopa treatment during the afternoon hours

Thomas, Ilias; Memedi, Mevludin; Westin, Jerker; Nyholm, Dag

doi:10.1111/ane.13020

Cited by 11 publications

(7 citation statements)

References 23 publications

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“…Altered threshold for levodopa responses during the day has been suggested as the possible mechanism of the afternoon “off”, consistent with the fact that patients on LCIG suffering from the afternoon “off”, including our case, usually require either extra doses or higher infusion rates during the latter part of the day [ 4 ]. The nature of the threshold also remains to be clarified, while the striatal pharmacodynamic changes could play a role [ 4 , 6 ]. Indeed, motor fluctuations are thought to be related to alterations in the striatal dopaminoceptive medium spiny GABAergic neurons and their synaptic connections with other striatal interneurons and cortical afferents that provide glutamatergic input [ 9 ].…”

Section: Beyond Wearing-off : Additional Factors Involved In the Underlying Mechanism Of Motor Fluctuationssupporting

confidence: 75%

“…Although the pathophysiology of the afternoon “off” during LCIG remains poorly understood [ 4 ], most of the peripheral factors are supposed to be resolved with LCIG on the basis of its mechanism of action. Altered threshold for levodopa responses during the day has been suggested as the possible mechanism of the afternoon “off”, consistent with the fact that patients on LCIG suffering from the afternoon “off”, including our case, usually require either extra doses or higher infusion rates during the latter part of the day [ 4 ]. The nature of the threshold also remains to be clarified, while the striatal pharmacodynamic changes could play a role [ 4 , 6 ].…”

Section: Beyond Wearing-off : Additional Factors Involved In the Underlying Mechanism Of Motor Fluctuationsmentioning

confidence: 99%

“…In theory, LCIG generates sustained stimulation of striatal neurons through consistent plasma concentration of levodopa by providing a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube [ 3 ]. Strangely, it has been reported that PD patients on LCIG are often troubled by motor fluctuations during the afternoon hours, even with stable plasma concentration of levodopa [ 4 ]. Here we offer a hypothesis that cholinergic signaling might also play a role in the pathophysiology of motor fluctuations, based on the authors' clinical experience as described below and review of the literature.…”

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confidence: 99%

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What can we learn from the effect of trihexyphenidyl on motor fluctuations during continuous levodopa-carbidopa intestinal gel infusion (LCIG)? – First documented case

Kubo¹,

Nakamura²,

Tada³

et al. 2020

Clinical Parkinsonism & Related Disorders

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Motor fluctuations can be seen even during treatment with continuous levodopa-carbidopa intestinal gel infusion (LCIG). We report on a middle-aged man with advanced Parkinson's disease (PD) on LCIG in which motor fluctuations have been improved with an anticholinergic. To the best of our knowledge, there have been no previous LCIG cases reported with motor fluctuations responding to non-dopaminergic agent, which might reveal some clues to its pathophysiology. Long-term oral levodopa treatment is associated with development of potentially disabling motor complications including motor fluctuations and dyskinesias in the majority of patients with PD. It has been suggested that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent administration of standard oral levodopa. LCIG significantly reduces “off” time and increases “on” time without dyskinesia in comparison to standard oral levodopa through consistent plasma concentration of levodopa to restore brain dopamine in a more physiological manner. However, it has been reported that PD patients on LCIG often worsen during the afternoon hours, even with stable plasma concentration of levodopa. This raises the possibility that additional factors to dopamine deficiency could play a role in occurrence of motor fluctuations. Here we offer a hypothesis that altered cholinergic signaling could also be involved in the pathophysiology of motor fluctuations, based on our clinical evidence that anticholinergic drug has eliminated motor fluctuations during LCIG in a patient with PD. Further studies for non-dopaminergic along with dopaminergic signaling may be needed to better understand the pathophysiological basis of motor complications in PD.

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Section: Beyond Wearing-off : Additional Factors Involved In the Underlying Mechanism Of Motor Fluctuationssupporting

confidence: 75%

Section: Beyond Wearing-off : Additional Factors Involved In the Underlying Mechanism Of Motor Fluctuationsmentioning

confidence: 99%

mentioning

confidence: 99%

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What can we learn from the effect of trihexyphenidyl on motor fluctuations during continuous levodopa-carbidopa intestinal gel infusion (LCIG)? – First documented case

Kubo¹,

Nakamura²,

Tada³

et al. 2020

Clinical Parkinsonism & Related Disorders

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“…Different flow rates during the day may be required in patients with diurnal fluctuations, which may occur in spite of the continuous infusion. 69 …”

Section: Practical Considerations For Treating Patients With Lecig In...mentioning

confidence: 99%

Levodopa–entacapone–carbidopa intestinal gel infusion in advanced Parkinson’s disease: real-world experience and practical guidance

Nyholm

Jost

2022

Ther Adv Neurol Disord

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As Parkinson’s disease (PD) progresses, treatment needs to be adapted to maintain symptom control. Once patients develop advanced PD, an optimised regimen of oral and transdermal medications may no longer provide adequate relief of OFF periods and motor complications can emerge. At this point, patients may wish to consider a device-aided therapy (DAT) that provides continuous dopaminergic stimulation to help overcome these issues. Levodopa–entacapone–carbidopa intestinal gel (LECIG) infusion is a recently developed DAT option. The aim of this article is twofold: (1) to give an overview of the pharmacokinetics of LECIG infusion and clinical experience to date of its use in patients with advanced PD, including real-world data and patient-reported outcomes from a cohort of patients treated in Sweden, the first country where it was introduced, and (2) based on that information to provide practical guidance for healthcare teams starting patients on LECIG infusion, whether they are transitioning from oral medications or from other DATs, including recommendations for stepwise dosing calculation and titration. In terms of clinical efficacy, LECIG infusion has been shown to have a similar effect on motor function to standard levodopa–carbidopa intestinal gel (LCIG) infusion but, due to the presence of entacapone in LECIG, the bioavailability of levodopa is increased such that lower overall levodopa doses can be given to achieve therapeutically effective plasma concentrations. From a practical standpoint, LECIG infusion is delivered using a smaller cartridge and pump system than LCIG infusion. In addition, for patients previously treated with LCIG infusion who have an existing percutaneous endoscopic transgastric jejunostomy (PEG-J) system, this is compatible with the LECIG infusion system. As it is a relatively new product, the long-term efficacy and safety of LECIG infusion remain to be established; however, real-world data will continue to be collected and analysed to provide this information and help inform future clinical decisions.

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“…A recent study has demonstrated that the maintenance dose of LCIG is strongly correlated with the mean plasma concentration of levodopa in the absence or presence of lunch, and comparison of the pharmacokinetic parameters showed that the coefficient of variation is significantly greater in fasting patients than in those that did eat [ 106 ]. Finally, it has been demonstrated that LCIG treatment is associated with high plasma levels of 3-O-methyldopa (3-OMD), a metabolite of levodopa (converted by catechol-O-methyltransferase [COMT]) which competes with levodopa itself for brain penetration, a phenomenon that can be counteracted by the concomitant administration of a COMT inhibitor [ 107 , 108 ]. However, even when all these factors are taken into consideration for optimization of LCIG administration, the persistence of ‘OFF’ periods is still commonly observed in everyday clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Why do ‘OFF’ periods still occur during continuous drug delivery in Parkinson’s disease?

Rota

Urso

Wamelen

et al. 2022

Transl Neurodegener

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Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson’s disease (PD) to control motor and non-motor fluctuations (‘OFF’ periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of ‘OFF’ periods. However, data suggest that despite their efficacy in reducing the number and duration of ‘OFF’ periods, these strategies still do not prevent ‘OFF’ periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent ‘OFF’ periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent ‘OFF’ periods unresponsive to dopaminergic therapy delivered via CDD.

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The effect of continuous levodopa treatment during the afternoon hours

Abstract: The results from all studies were consistent, both in the proportion of patients in the three groups and in the value of TRS decrease in the afternoon hours. Based on these findings, there seems to be a group of patients with predictable "off" behavior in the later parts of the day.

Cited by 11 publications

References 23 publications

What can we learn from the effect of trihexyphenidyl on motor fluctuations during continuous levodopa-carbidopa intestinal gel infusion (LCIG)? – First documented case

What can we learn from the effect of trihexyphenidyl on motor fluctuations during continuous levodopa-carbidopa intestinal gel infusion (LCIG)? – First documented case

Levodopa–entacapone–carbidopa intestinal gel infusion in advanced Parkinson’s disease: real-world experience and practical guidance

Why do ‘OFF’ periods still occur during continuous drug delivery in Parkinson’s disease?

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