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Twenty Years of Apomorphine Therapy – How Does it Compare with Levodopa?

European Neurological Review, 2014;9(2):113-9 DOI: http://doi.org/10.17925/ENR.2014.09.02.113

Abstract:

Apomorphine administered subcutaneously has provided clinicians with an effective option for the rapid resolution of the symptoms of Parkinson’s disease (PD) for over a quarter of a century. It is available for use either as an intermittent injection or a continuous infusion, depending on the severity of the patient’s symptoms. This satellite symposium, held during the 18th International Congress of Parkinson’s Disease and Movement Disorders in Stockholm, Sweden, from 8–12 June 2014, and chaired by Professor Andrew Lees, set out to review the extensive clinical experience of subcutaneous apomorphine in the management of PD accumulated over the past 25 years. It also aimed to explore why it continues to play such a valuable therapeutic role in this setting. The presenters highlighted key clinical data demonstrating why apomorphine is an effective choice for the management of both motor and non-motor symptoms in PD. Results from the limited number of comparative studies of apomorphine continuous infusion with other therapies for complex PD suggest that it has a robust motor effect, resulting in a reduction of OFF periods comparable to that achieved with more invasive options such as intrajejunal levodopa infusion or deep brain stimulation. In a large European study, apomorphine infusion has been shown to provide similar improvements in health-related quality of life to intrajejunal levodopa infusion but with a superior side-effect profile. In addition, apomorphine infusion has demonstrated beneficial non-motor effects in PD patients and reports suggest it is associated with low rates of impulse control disorders (ICDs). The motor fluctuations that occur over time in PD patients treated with oral levodopa present a management challenge as the disease progresses. Many PD patients experience these OFF periods despite optimised oral therapy and the use of multiple medications. They are due to both end-of-dose wearing OFF and delayed time to ON (TTO). A prolonged TTO is common in PD patients who have gastroparesis (delayed gastric emptying) whereby the levodopa dose is delayed exiting the stomach and is slow in reaching its site of absorption in the small intestine. Alternative non-oral formulations that avoid the gastrointestinal route, such as subcutaneous apomorphine intermittent injection, have therefore been investigated for the relief of motor fluctuations in this setting. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study have shown that subcutaneous apomorphine injection is a valuable treatment option in PD patients with morning akinesia. This is due to a delayed onset of levodopa dose as it produces a rapid and reliable TTO, with 95 % of patients achieving at least a 20-minute reduction in TTO and an average reduction of 40 minutes. Patients also experienced improvements in Unified Parkinson’s Disease Rating Scale (UPDRS) motor score and Hoehn and Yahr stage, as well as measures of quality of life and global impression of severity.

Keywords: Parkinson’s disease (PD), motor fluctuations, morning akinesia, gastroparesis, levodopa, subcutaneous apomorphine
Disclosure: Andrew Lees is a consultant for Britannia and has received honoraria from, and served on advisory boards for Bial, Boehringer-Ingelheim, Britannia, Lucid, Lundbeck, GSK, Ipsen, Novartis, Orion, Roche and Teva and. K Ray Chaudhuri has received honoraria for sponsored symposia in educational meetings from AbbVie, Britannia, Mundipharma, Otsuka, UCB and US World Meds. He has received educational grants from AbbVie, Britannia, Medtronic and UCB. 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 WorldMeds.
Acknowledgments: Editorial assistance was provided by Dr Karen Wolstencroft, Helen Lawn Associates, supported by Britannia Pharmaceuticals Ltd.
Received: October 10, 2014 Accepted: November 07, 2014
Correspondence: Professor Andrew Lees, Emeritus Director, Reta Lila Weston Institute, UCL Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ United Kingdom. E: andrew.lees@ucl.ac.uk
Support: The publication of this article was supported by Britannia Pharma. The views and opinions expressed are those of the authors and not necessarily those of Britannia Pharma.

Introduction to Apomorphine and its Role in the Treatment of Parkinson’s Disease

Andrew Lees

Professor of Neurology, National Hospital for Neurology and Neurosurgery, London.

Apomorphine is a highly-potent dopamine agonist (DA) that, unlike other clinically available compounds in this class, selectively acts on both D1 and D2 dopamine receptors and has been shown in a number of published clinical trials to achieve antiparkinsonian efficacy comparable to that of orally administered levodopa.1 As far back as the 1950s, apomorphine was used to treat PD, long before its dopaminergic properties were fully understood and levodopa was developed.2 Subsequently, in the late 1960s, Cotzias and colleagues, aware of some of the shortcomings of levodopa in PD treatment, began to investigate other dopaminergic compounds and conducted clinical investigations into apomorphine in PD patients. They found that tremor responded well to apomorphine therapy, that it reduced dyskinesias in levodopa-treated patients and that it had possible anti-psychotic properties.3 The product was not developed further at that time as a therapy for PD, possibly due to both the emergence of oral dopaminergic drugs and the reluctance of neurologists to use an injectable formulation, but also due to its emetic properties. Subsequently, as a result of new pump technology in the field of diabetes and the availability of the anti-emetic domperidone, a clinical trial of apomorphine infusion for the management of Parkinsonian ON-OFF oscillations was undertaken by Stibe and colleagues.4 Published in 1988, this pivotal trial confirmed that apomorphine was the only clinically available DA that was equipotent to levodopa and it was subsequently licensed for the treatment of PD in the UK. Since that time, a range of randomised, controlled clinical trials (using apomorphine injection) and open, uncontrolled studies (using apomorphine infusion) have confirmed it as a highly effective therapy to help manage refractory motor fluctuations, with thousands of PD patients throughout the world benefitting from its use. Apomorphine infusion has also been shown to improve drug-induced dyskinesias, allowing a reduction in the oral levodopa dose.5 Nowadays, apomorphine is recognised by clinicians as an established therapy, backed by many patient-years of experience, which still has considerable value in helping to manage the complex problems they face in treating PD patients in their daily clinical practice.

This satellite symposium, held during the 18th International Congress of Parkinson’s Disease and Movement Disorders, reviewed the extensive clinical experience with subcutaneous apomorphine in PD patients that has accumulated over the past 25 years and explored why it continues to play such a valuable role in treatment of this disease.

While the management of PD focuses primarily on addressing motor symptoms, there is also a broad range of non-motor symptoms (NMS) that compromise health-related quality of life (QoL) in PD patients.6–8 In his presentation, Professor K Ray Chaudhuri discussed comparative data on both motor and non-motor effects of conventional non-oral/ transdermal therapies in advanced PD and the reported beneficial effects of subcutaneous apomorphine in this setting, particularly in terms of its side-effect profile in comparison to other agents.

Morning akinesia is a common but under-recognised symptom in PD patients, which occurs in almost 60 % of subjects9 and results from a delay in time to ON (TTO) of the first daily dose of levodopa. Professor Stuart Isaacson reviewed the interim results from the ongoing AM-IMPAKT study that demonstrate that subcutaneous apomorphine injection results in a rapid and reliable TTO in these patients, with significant improvements in QoL.

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Keywords: Parkinson’s disease (PD), motor fluctuations, morning akinesia, gastroparesis, levodopa, subcutaneous apomorphine