The 8th World Congress on Controversies in Neurology (CONy) held in Berlin in May 2014 provided a forum for neurologists and other healthcare professionals to debate some of the most significant and controversial topics facing clinicians in the field of neurology. The Britannia-sponsored debate session on Parkinson’s Disease Treatment tackled some key questions about the role of apomorphine in the management of PD.

Should patients with early morning akinesia have an apomorphine injection as their first daily dose?

Debated by: Stuart Isaacson¹,Claudia Trenkwalder² and Irena Rektorova³

¹Florida International University, Herbert Wertheim College School of Medicine, Miami; Director, Parkinson’s Disease and Movement Disorders Center of Boca Raton; Research Director, Marcus Neuroscience Institute, Boca Raton Regional Hospital, Florida, USA.

²University of Goettingen, Paracelsus-Elena Klinik, Kassel, Germany.

³Department of Neurology, Masaryk University, Brno, Czech Republic.

 

YES – Stuart Isaacson (USA)

When selecting therapy for Parkinson’s disease (PD) patients who have morning akinesia Professor Isaacson considered that apomorphine pen injection was the best available option as it provided the most rapid and reliable time to ON (TTO), allowing patients to get on with their daily activities. The extensive clinical experience with apomorphine pen injection over the past 20 years has confirmed that it is well tolerated by PD as well as being quick and easy for them to use (Figure 1). He recognised that while there might be some initial reluctance to use an injectable formulation, this method is in fact widely used by patients of all ages for many different conditions nowadays, including diabetes, osteoporosis, arthritis and multiple sclerosis.

 

Figure 1: Apomorphine pen injection.

Levodopa is the mainstay of PD management and with initial treatment the clinical effect of each levodopa dose is typically rapid, reliable and sustained with an onset of effect of around 20 minutes and a long duration response. However, within several years of initiation of levodopa treatment, the duration of response becomes progressively shorter and OFF periods occur with increasing frequency (1, 2). These OFF periods have traditionally been considered as due to end-of-dose wearing off but more recently delayed TTO and dose failures have been recognised as significant contributors to total OFF time. A study in 20 PD patients with motor fluctuations found that TTO was in fact more than twice the duration of wearing off (3). OFF periods can occur despite optimised oral therapy which impacts the patient’s daily routine and reduces their quality of life (QoL) (4, 5).

Morning akinesia is a common but under-recognised symptom in patients with Parkinson’s disease (PD) and results from a delay in time to ON (TTO) of the first daily dose of levodopa. Studies have shown that early morning OFF periods are frequent across all stages of PD, occurring in almost 60{cf2c27d335602139ec9071daca508545599ba8f9ca09b366fd00e5c28736f208} of patients (4, 6, 7). As a consequence, a large proportion of PD patients are likely to have difficulties managing their usual morning routine due to debilitating motor and non-motor symptoms (NMS) and require additional therapy to ensure that they achieved an ON state when they wake up. Despite the frequency of this condition and the fact that it can be easily and rapidly resolved with the apomorphine pen injection, Professor Isaacson was concerned that treatment remains suboptimal.

Professor Isaacson highlighted the fact that gastrointestinal (GI) dysfunction, including gastroparesis (delayed gastric emptying), is a common feature of PD throughout the course of the disease and often occurs before motor symptoms are evident. A survey of PD patients found that 24{cf2c27d335602139ec9071daca508545599ba8f9ca09b366fd00e5c28736f208} reported nausea and 45{cf2c27d335602139ec9071daca508545599ba8f9ca09b366fd00e5c28736f208} reported bloating (8), classic symptoms of gastroparesis. In addition to causing these GI symptoms gastroparesis is also a causative factor in delayed TTO (9) – motor fluctuations occur as a result of the delayed emptying of oral levodopa from the stomach and its arrival at the site of absorption in the small intestine (10, 11). In fact, Professor Isaacson considered that delayed ON and dose failure can also be considered as symptoms of gastroparesis and such patients should be investigated further. Impaired intestinal absorption of levodopa may also occur due to dietary protein effects – so called ‘postprandial OFF’ – or bacterial overgrowth (12-14).

Professor Isaacson highlighted that is was not just motor symptoms that occurred during early morning OFF periods in PD patients. As shown by the recent EUROPAR study, NMS, such as urinary urgency, anxiety, dribbling and pain, were also common (6) and these also impact on the patient’s quality of life (4).

Various strategies to improve delayed ON and morning akinesia have been investigated including the use of dispersible or modified-release levodopa formulations or adjunctive therapies such as MAO inhibitors and long-acting dopamine agonists, such as rotigotine patch. However, while these approaches can decrease the severity of the morning akinesia OFF state, they do not result in a rapid or reliable TTO (15-18). In light of the various problems with GI issues in PD that cause this delay in TTO, in his opinion the best option is to select a non-oral therapy that bypasses the GI route, such as subcutaneous apomorphine injection. Apomorphine injection provides similar improvements in motor symptoms and NMS to levodopa but acts more rapidly (19).

Professor Isaacson reported that the effectiveness of apomorphine injection have been confirmed by interim results of the ongoing AM-IMPAKT (Apokyn for Motor IMProvement of Morning Akinesia Trial) which found that apomorphine injection significantly improved TTO in PD patients with morning akinesia due to a delayed onset of levodopa dose, and was both rapid and reliable with 95{cf2c27d335602139ec9071daca508545599ba8f9ca09b366fd00e5c28736f208} of patients achieving at least a 20-minute reduction in TTO with an average reduction of 40 minutes (Figure 2) (20).

Figure 2: Average reduction of 40 minutes in time-to-ON following apomorphine injection.

Analysis of individual patient data shows the reliability of the response to apomorphine (Figure 3) – practically every patient has a rapid and reliable clinical improvement.

Figure 3: Reliable reduction in average daily time-to-ON in individual patients following apomorphine injection.

These motor symptom improvements were also reflected in measures of health-related quality of life (Figure 4). EQ-5D-3L index scores were significantly reduced from a mean of 3.50 at baseline to a mean of 2.31 at the end of the treatment period (p<0.0001). EQ-5D-3L is a patient-reported health outcome scale related to mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension is ranked from 1 (no problem) to 5 (extreme problem) so lower scores indicate a more favourable rating. Similarly, EQ-5D VAS scores significantly improved from a mean of 48.02 at baseline to 65.25 at the end of the treatment period (p=0.0001). Using this scale, subjects rate their health state relative to akinesia on a scale of 0 (worst imaginable] to 100 (best imaginable) so higher scores indicate a more favourable rating.

Figure 4: Improvements in measure of health-related quality of life following apomorphine injection.

Professor Isaacson concluded his talk by summarising that apomorphine injection was an ideal therapy for morning akinesia for the following reasons:

• Provides a robust response with equivalent efficacy to levodopa in resolving OFF periods and superior efficacy to rotigotine or rasagiline
• Rapid onset of action from as early as 7.5 minutes (21)
• Reliable efficacy, avoiding the GI tract
• 20 years of use in ~5000 patients worldwide have confirmed its safety and tolerability
• Quick and easy to use with a relatively painless, simple injection device

NO – Professor Claudia Trenkwalder (Germany) considered that careful patient selection was extremely important when deciding the most appropriate therapy in PD. Firstly, she outlined the patient population who suffered from morning akinesia, namely those at moderate or advanced stage of PD who were already experiencing motor fluctuations. The phenomenon of morning akinesia reflected the nocturnal decline in levels of dopaminergic medication and insufficient night-time storage or insufficient refreshing of the dopaminergic system during the night-time and during sleep. This manifests as motor problems on awakening but also resulted in night-time akinesia and sleep problems.

Professor Trenkwalder recommended that the initial strategy should be to increase the nocturnal dopaminergic storage with appropriate bedtime medications to improve both nocturnal and early morning akinesia. She felt this could be achieved with sustained-release levodopa preparations or long-acting dopamine agonists that have night-time efficacy.

As an example of the use of a long-acting dopamine agonist, Professor Trenkwalder highlighted the results of the RECOVER study which assessed the effects of 24-hour transdermal delivery of rotigotine on control of early morning motor function and sleep disorders in patients with idiopathic PD (15). Results showed that both Unified Parkinson’s Disease Rating Scale (UPDRS) scores assessed in the early morning before levodopa intake significantly improved as did the PDSS-2 scores (a subjective assessment of disturbed sleep, motor symptoms and PD symptoms at night) for both nocturnal akinesia and morning akinesia.

Some patients might also benefit from additional sustained-release oral levodopa during the night or soluble levodopa on awakening to resolve nocturnal and early morning akinesia. Professor Trenkwalder reported that controlled clinical trials assessing the benefits of sustained-release levodopa compared with standard levodopa taken at bedtime were limited (22, 23) however despite the lack of trial data, clinical experience over many years has suggested the benefits of this approach.

There were also few data regarding early morning use of soluble levodopa however it was widely used in PD patients as early morning ‘starter’ and rescue medication. She reported a double-blind, single-dose study that had compared the latency and effect duration of subcutaneous apomorphine and dispersible levodopa in PD patients (24). Twelve parkinsonian patients with severely fluctuating symptoms were given a single dose of apomorphine or dispersible levodopa on two consecutive days. Apomorphine proved faster in reverting morning OFF periods in this setting however in Professor Trenkwalder’s experience in the clinic, many patients did not want to use it despite its rapid effect.

Despite the lack of controlled clinical trial data, in her hospital Professor Trenkwalder reported that 80{cf2c27d335602139ec9071daca508545599ba8f9ca09b366fd00e5c28736f208} of fluctuating PD patients use soluble levodopa. In many cases, patients did not agree to the withdrawal of immediate-release levodopa and doing so can have an impact on compliance with therapy.

Taking the patient’s viewpoint, she considered some of the practical advantages of soluble levodopa for morning akinesia: it is easy to handle, the patient can take the tablet unaided, the latency period before it has an effect is about 15–20 minutes, which should not be a problem in the early morning after awakening, and patients can take additional tablets during the night. She considered that the possible disadvantages of apomorphine injection were that during a period of severe akinesia the patient may not able to use the pen without help. She added that a drop in blood pressure in the early morning, especially in very old patients, was more likely after apomorphine than levodopa.

Professor Trenkwalder concluded that the therapeutic approach for morning akinesia should be kept simple: use either nighttime dopaminergic stimulation or early morning soluble levodopa or both.

Commentary – Professor Irena Rektorova (Czech Republic) reviewed the presentations and summarised the pros and cons of these two alternative viewpoints, recognising the challenges commonly faced by oral levodopa administration to PD patients in terms of impaired gastric emptying, reduced intestinal absorption, and competition for active transport across the blood–brain barrier (25). These issues can be partly addressed by adjustments to diet and the timing of levodopa doses however they do not overcome the problem of gastroparesis which is common in PD patients. Soluble and dispersible formulations have been tried in this setting in a few studies but with limited success and very few trials to confirm their usefulness. Transdermal rotigotine patch has been shown to decrease the severity of the morning akinesia OFF state and improve sleep symptoms but does not ensure the patient is fully ON.

Professor Rektorova noted that apomorphine is the most potent of the available dopamine agonists, it bypasses GI absorption problems, and there is no competition with circulating proteins for access to the CNS. In addition, it has a rapid and reliable onset of action from as early as 7.5 minutes.

It was recognised however that each PD patient was different and warranted individualised treatment. The selection of the most appropriate strategy to combat morning akinesia should be based on their own specific symptoms and personal choice of treatment to suit their own circumstances.

References

1. Melamed E, Bitton V, Zelig O. Delayed onset of responses to single doses of L-dopa in parkinsonian fluctuators on long-term L-dopa therapy. Clin Neuropharmacol 1986;9:182-188.

2. Marsden CD, Parkes JD. “On-off” effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet 1976;1:292-296.

3. 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;26:196-198.

4. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005;20:224-230.

5. Isaacson S, Chaudhuri KR. Morning akinesia and the potential role of gastroparesis – managing delayed onset of first daily dose of oral levodopa in patients with Parkinson’s disease. European Neurological Review 2013;8:82-84.

6. Rizos A, Kessel B, Martinez-Martin P, Odin P, Antonini A, Martin A, Gallagher L, et al. Early morning off periods in Parkinson’s disease: Characterisation of non motor patterns and treatment effect: An international study. In: 9th International Congress on Mental Dysfunction and other Non-Motor Features in Parkinson’s Disease and Related Disorders. Seoul, Korea; 2013.

7. Wullner U, Fuchs G, Reketat N, Randerath O, Kassubek J. Requirements for Parkinson’s disease pharmacotherapy from the patients’ perspective: a questionnaire-based survey. Curr Med Res Opin 2012;28:1239-1246.

8. Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2003;2:107-116.

9. Doi H, Sakakibara R, Sato M, Masaka T, Kishi M, Tateno A, Tateno F, et al. Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease. J Neurol Sci 2012;319:86-88.

10. Nyholm D, Lennernas H. Irregular gastrointestinal drug absorption in Parkinson’s disease. Expert Opin Drug Metab Toxicol 2008;4:193-203.

11. Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson’s disease. Mov Disord 2014;29:23-32.

12. Fernandez N, Garcia JJ, Diez MJ, Sahagun AM, Diez R, Sierra M. Effects of dietary factors on levodopa pharmacokinetics. Expert Opin Drug Metab Toxicol 2010;6:633-642.

13. Cereda E, Barichella M, Pezzoli G. Controlled-protein dietary regimens for Parkinson’s disease. Nutr Neurosci 2010;13:29-32.

14. Fasano A, Bove F, Gabrielli M, Petracca M, Zocco MA, Ragazzoni E, Barbaro F, et al. The role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov Disord 2013;28:1241-1249.

15. Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, Dioszeghy P, 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;26:90-99.

16. Giladi N, Fichtner A, Poewe W, Boroojerdi B. Rotigotine transdermal system for control of early morning motor impairment and sleep disturbances in patients with Parkinson’s disease. J Neural Transm 2010;117:1395-1399.

17. Stocchi F, Rabey JM. Effect of rasagiline as adjunct therapy to levodopa on severity of OFF in Parkinson’s disease. Eur J Neurol 2011;18:1373-1378.

18. Elmer LW. Rasagiline adjunct therapy in patients with Parkinson’s disease: post hoc analyses of the PRESTO and LARGO trials. Parkinsonism Relat Disord 2013;19:930-936.

19. 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, placebo-controlled crossover evaluation of a single dose. J Neurol Sci 2007;258:137-143.

20. Isaacson S. AM IMPAKT Study interim results. In: International Parkinson and Movement Disorder Society. Treatment of Parkinson’s disease: past, present and future. Miami, Florida, USA; 2014.

21. LeWitt PA. Subcutaneously administered apomorphine: pharmacokinetics and metabolism. Neurology 2004;62:S8-11.

22. A comparison of Madopar CR and standard Madopar in the treatment of nocturnal and early-morning disability in Parkinson’s disease. The UK Madopar CR Study Group. Clin Neuropharmacol 1989;12:498-505.

23. Sage JI, Mark MH. Comparison of controlled-release Sinemet (CR4) and standard Sinemet (25 mg/100 mg) in advanced Parkinson’s disease: a double-blind, crossover study. Clin Neuropharmacol 1988;11:174-179.

24. Merello M, Pikielny R, Cammarota A, Leiguarda R. Comparison of subcutaneous apomorphine versus dispersible madopar latency and effect duration in Parkinson’s disease patients: a double-blind single-dose study. Clin Neuropharmacol 1997;20:165-167.

25. Swope DM. Rapid treatment of “wearing off” in Parkinson’s disease. Neurology 2004;62:S27-31.

APO2-0614-0491 Date of Preparation: June 2014

Prescribing information can be here: http://www.apo-go.co.uk/hcp/prescribing-information .