Enhancing Patient Outcomes with Current Therapies – Practical Approaches to Treatment Optimisation in Parkinson’s Disease

European Neurological Review, 2016;11(Suppl.3):2–7


Despite taking multiple oral medications to control the symptoms of Parkinson’s disease (PD), many patients experience significant OFF time each day, with troublesome motor fluctuations and dyskinesias, that impact their quality of life. This symposium, chaired by Claudia Trenkwalder (Germany), set out to review the most practical and effective approaches to enhance the outcomes of PD patients across all disease stages using currently available therapies. Stuart Isaacson (US) discussed how to optimise ON time in PD patients once fluctuations start. He highlighted the importance of considering non-oral routes of administration of PD medication to avoid gastrointestinal issues that are common in PD and can affect medication absorption. He reviewed the results of the AM-IMPAKT (Apokyn for Motor IMProvement of morning AKinesia Trial) study, which demonstrated that delayed ON and dose failure due to poor absorption of oral levodopa can be rapidly and reliably overcome with subcutaneous apomorphine injection. Georg Ebersbach (Germany) considered the later stages of disease and the management of patients who require continuous dopaminergic stimulation. Using case study illustrations, he advised how to select the correct form of advanced therapy for patients, highlighting the importance of continuous review and monitoring to optimise their outcomes.
Keywords: Parkinson’s disease, motor fluctuations, levodopa, subcutaneous apomorphine injection, subcutaneous apomorphine infusion
Disclosure: Claudia Trenkwalder has received personal fees for advisory boards from Mundipharma, UCB, Vifor Pharma, Britannia Pharmaceuticals, Novartis; payments for lectures from UCB, Astra Zeneca, Desitin, Mundipharma, Abbvie; royalties from Schattauer Verlag. Stuart H Isaacson has received honoraria for CME activities, research grants and/or consultant and promotional speaker fees from AbbVie, Acadia, Adamas, Addex, Allergan, Allon, AstraZeneca, Biotie, Britannia, Chelsea, Civitas, Eisai, GE, GSK, Impax, Ipsen, Kyowa, Lilly, Merck Schering-Plough, Medtronics, Merz, Michael J Fox Foundation, Novartis, Neurocrine, National Institutes of Health (NIH), Novartis, Orion, Parkinson Study Group, Phytopharm, Purdue, Roche, Santhera, Serono, Shire, Teva, UCB and US World Meds. Georg Ebersbach has received consultancies from AOK Nordost; honoraria for advisory boards from UCB Pharma, AbbVie Pharma, Grünenthal Pharma; speaker’s honoraria from AbbVie Pharma, Britannia Pharma, Desitin Pharma, Grünenthal Pharma, Licher GmbH, Mundipharma, TEVA Pharma, UCB Pharma, Zambon Pharma; royalties from Kohlhammer Verlag. This article reports the proceedings of a sponsored satellite symposium held at the 20th International Congress of Parkinson’s Disease and Movement Disorders, Berlin, Germany and, as such, has not been subject to this journal’s usual peer-review process. A member of the editorial board reviewed the report before publication.
Acknowledgments: Writing assistance was provided by Dr Karen Wolstencroft, Helen Lawn Associates PR Limited, funded by Britannia Pharmaceuticals Limited.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: September 14, 2016
Correspondence: Claudia Trenkwalder, Paracelsus-Elena Hospital, Centre of Parkinsonism and Movement Disorders, Klinikstr. 16, DE-34128 Kassel, Germany. Email: ctrenkwalder@gmx.de
Support: The publication of this article was funded by Britannia Pharmaceuticals Limited

Professor Trenkwalder considered that the challenge of how to enhance outcomes for patients was a key focus of clinical care for all clinicians who treated patients with Parkinson’s disease (PD). However, despite receiving multiple medications, many patients with PD find that their symptoms are not adequately controlled. Commonly, they complain about experiencing motor OFF periods with akinesia, which impact on their quality of life (QoL) and their ability to undertake their daily activities.1

Motor OFF periods that occur upon awakening (early morning OFF [EMO] periods) are often the first manifestation of motor fluctuations. They are known to be common in PD patients2,3 and can interfere with their ability to undertake their usual morning routine – getting out of bed, having a shower etc. – as well as having a significant negative impact on their QoL.2 EUROPAR was an international, multicentre, observational study of 320 PD patients receiving dopaminergic therapy that investigated the prevalence and characteristics of EMO periods.3 The results showed that EMO periods were present in 60% of PD patients in the study and occurred throughout the course of the disease at all stages: mild, moderate and severe. Importantly, at least half of patients who were already being treated with optimised dopaminergic therapy still experienced EMO periods.

Despite the persistence of motor problems, as their PD progresses, many patients remain on oral therapies when in fact their symptoms suggest they would be better suited to a more advanced therapy which would give them continuous dopaminergic stimulation. It seems there is a need for clinicians to give their patients a better explanation of advanced treatment options available to them at this point, such as subcutaneous apomorphine infusion, intrajejunal levodopa infusion and deep-brain stimulation, so that together they can make an informed treatment decision that best suits the individual patient’s needs and may reduce their negative feelings or hesitation about trying non-oral treatments.

In an effort to encourage a more ‘tailored’ approach to treatment, the European Parkinson’s Disease Association (EPDA) Inventory has recently been established which aims to identify gaps in the current PD care pathways and to seek out national examples of good practice (www.epda.eu.com/en/projects/my-pd-journey/work-programme/ european-inventory/).

The focus of this symposium was therefore to discuss what clinicians can do to better optimise therapy for PD patients in their care, using the currently available treatment options. The presentations focused firstly on how best to manage patients when fluctuations first start and then discussed patients with more advanced disease experiencing severe and frequent OFF periods. In each case the presenters highlighted the practical issues facing clinicians in their daily practice including how to select which treatment is best suited for each patient and, once they are established on therapy, how best to monitor them to ensure the best possible outcomes.

Optimising ON Time When Fluctuations Start
As their disease progresses, many PD patients experience motor fluctuations and increasing periods of OFF time, even though they may be taking a range of different PD medications. In the early stages of levodopa treatment – the ‘gold standard’ PD therapy – the clinical effect is typically rapid, reliable and sustained, and patients experience excellent benefits in terms of symptom control. However, with long-term treatment and disease progression, the duration of benefit of each levodopa dose becomes progressively shorter and patients begin to experience fluctuations in motor function, alternating between ON responses with a good antiparkinsonian effect and OFF responses when levodopa does not adequately treat their motor symptoms.4,5 The clinical effects begin to mimic the pharmacokinetics of levodopa and its short half-life in the plasma. Motor fluctuations can include end-of-dose wearing off, a delay in the time taken to turn ON, suboptimal ON, dose failure (no-ON), morning akinesia, postprandial OFF, and nocturnal akinesia. In some cases, patients can experience rapid oscillations between ON and OFF states (ON–OFF phenomena) without an apparent association with the levodopa dose.

Professor Isaacson considered that the development of motor fluctuations is a key limitation to the long-term management of PD with levodopa. Within five years of starting oral levodopa therapy 38–50% of patients develop motor fluctuations6–8 which can impact significantly on their ability to function and their overall QoL.2,9 While motor fluctuations are classically associated with the later stages of PD, they also occur in early disease. Patients with early disease, presenting as well controlled, may in fact already be experiencing fluctuations in their response to levodopa and this has consequences for the patient’s long-term outcome and choice of therapy.

1. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease, Mov Disord, 2011;26:399–406.
2. Chapuis S, Ouchchane L, Metz O, et al., Impact of the motor complications of Parkinson’s disease on the quality of life, Mov Disord, 2005;20:224–30.
3. Rizos A, Martinez-Martin P, Odin P, et al., Characterizing motor and non-motor aspects of early-morning off periods in Parkinson’s disease: an international multicenter study, Parkinsonism Relat Disord, 2014;20:1231–5.
4. Stocchi F, The hypothesis of the genesis of motor complications and continuous dopaminergic stimulation in the treatment of Parkinson’s disease, Parkinsonism Relat Disord, 2009;15 (Suppl 1):S9–S15.
5. Stocchi F, Jenner P, Obeso JA, When do levodopa motor fluctuations first appear in Parkinson’s disease?, Eur Neurol, 2010;63:257–66.
6. Parkinson Study Group, Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group, JAMA, 2000;284:1931–8.
7. Fahn S, Does levodopa slow or hasten the rate of progression of Parkinson’s disease?, J Neurol, 2005;252(Suppl 4):IV37–42.
8. Jankovic J, Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations, Mov Disord, 2005;20(Suppl 11):S11–16.
9. Muller B, Assmus J, Herlofson K, et al., Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson’s disease, Parkinsonism Relat Disord, 2013;19:1027–32.
10. Manson A, Stirpe P, Schrag A, Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life, J Parkinsons Dis, 2012;2:189–98.
11. Colzi A, Turner K, Lees AJ, Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease, J Neurol Neurosurg Psychiatry, 1998;64:573–6.
12. Merims D, Djaldetti R, Melamed E, Waiting for ON: a major problem in patients with Parkinson disease and ON/OFF motor fluctuations, Clin Neuropharmacol, 2003;26:196–8.
13. Fox SH, Katzenschlager R, Lim SY, et al., The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson’s disease, Mov Disord, 2011;26(Suppl 3):S2–41.
14. Ondo WG, Shinawi L, Moore S, Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single-dose, double-blind, doubledummy, placebo-controlled, crossover trial, Mov Disord, 2010;25:2724–7.
15. Monge A, Barbato L, Nordera G, Stocchi F, An acute and long-term study with a dispersible formulation of levodopa/ benserazide (Madopar®) in Parkinson’s disease, Eur J Neurol, 2011;4:485–90.
16. Stocchi F, Rabey JM, Effect of rasagiline as adjunct therapy to levodopa on severity of OFF in Parkinson’s disease, Eur J Neurol, 2011;18:1373–8.
17. Trenkwalder C, Kies B, Rudzinska M, et al., Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER), Mov Disord, 2011;26:90–9.
18. Pfeiffer RF, Gastrointestinal dysfunction in Parkinson’s disease, Lancet Neurol, 2003;2:107–16.
19. Chana P, Kuntsmann C, Reyes-Parada M, Saez-Briones P, Delayed early morning turn “ON” in response to a single dose of levodopa in advanced Parkinson’s disease: pharmacokinetics should be considered, J Neurol Neurosurg Psychiatry, 2004;75:1782–3.
20. Marrinan S, Emmanuel AV, Burn DJ, Delayed gastric emptying in Parkinson’s disease, Mov Disord, 2014;29:23–32.
21. Stocchi F, The levodopa wearing-off phenomenon in Parkinson’s disease: pharmacokinetic considerations, Expert Opin Pharmacother, 2006;7:1399–407.
22. Nyholm D, Lennernas H, Irregular gastrointestinal drug absorption in Parkinson’s disease, Expert Opin Drug Metab Toxicol, 2008;4:193–203.
23. Heetun ZS, Quigley EM, Gastroparesis and Parkinson’s disease: a systematic review, Parkinsonism Relat Disord, 2012;18:433–40.
24. Doi H, Sakakibara R, Sato M, et al., Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease, J Neurol Sci, 2012;319:86–8.
25. Isaacson S, Lew M, Ondo W, Apomorphine Subcutaneous Injection for the Management of Morning Akinesia in Parkinson’s Disease, Mov Disord Clin Pract, 2016; doi:10.1002/ mdc3.12350.
26. Dewey RB, Jr, Hutton JT, LeWitt PA, Factor SA, A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events, Arch Neurol, 2001;58:1385–92.
27. Pfeiffer RF, Gutmann L, Hull KL, Jr, et al., Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease, Parkinsonism Relat Disord, 2007;13:93–100.
28. Pahwa R, Koller WC, Trosch RM, Sherry JH, Subcutaneous apomorphine in patients with advanced Parkinson’s disease: a dose-escalation study with randomized, double-blind, placebocontrolled crossover evaluation of a single dose, J Neurol Sci, 2007;258:137–43.
29. LeWitt PA, Ondo WG, Van Lunen B, Bottini PB, Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating “off” episodes in advanced Parkinson disease, Clin Neuropharmacol, 2009;32:89–93.
30. Pagan F, Isaacson S, Ondo W, Lew M, Apomorphine improves early morning motor function: Analysis of secondary endpoints in the AM‐IMPAKT trial [abstract], Mov Disord, 2015;30 (Suppl 1):284.
31. Ahlskog JE, Muenter MD, Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature, Mov Disord, 2001;16:448–58.
32. Quinn N, Critchley P, Marsden CD, Young onset Parkinson’s disease, Mov Disord, 1987;2:73–91.
33. Trenkwalder C, Chaudhuri KR, Garcia Ruiz PJ, et al., Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson’s disease - Clinical practice recommendations, Parkinsonism Relat Disord, 2015;21(9):1023–30.
34. Odin P, Ray Chaudhuri K, Slevin JT, et al., Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson’s disease: Consensus from an international survey and discussion program, Parkinsonism Relat Disord, 2015;21:1133–44.
35. Volkmann J, Albanese A, Antonini A, et al., Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review, J Neurol, 2013;260:2701–14.
36. Martinez-Martin P, Reddy P, Katzenschlager R, et al., EuroInf: A Multicenter Comparative Observational Study of Apomorphine and Levodopa Infusion in Parkinson’s Disease, Mov Disord, 2015;30:510–16.
37. Bhidayasiri R, Chaudhuri KR, LeWitt P, Effective delivery of apomorphine in the management of Parkinson disease: practical considerations for clinicians and Parkinson nurses, Clin Neuropharmacol, 2015;38:89–103.
38. Deleu D, Hanssens Y, Northway MG, Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease, Drugs Aging, 2004;21:687–709.
39. Steendam-Oldekamp TE, Rutgers AW, Buskens E, van Laar T, [Short-term rehabilitation of Parkinson’s disease patients delays nursing home placement], Ned Tijdschr Geneeskd, 2012;156:A4776.
Keywords: Parkinson’s disease, motor fluctuations, levodopa, subcutaneous apomorphine injection, subcutaneous apomorphine infusion