K. Ray Chaudhuri Professor of Movement Disorders, Director of the National Parkinson Foundation Centre of Excellence, Department of Neurology, King’s College and King’s College Hospital, and Kings Health Partners, London, UK
Many physicians who treat patients with Parkinson’s disease (PD) may not be aware that up to half of them could be suffering from treatable early-morning OFF (EMO) periods that can significantly impair their ability to get up in the morning and get on with their day (1).The symptoms, dominated by non-motor problems such as anxiety, pain and urinary urgency, often go unreported to the physician unless the patient is specifically questioned and therefore continue untreated, despite easy and effective options being available. EMO periods that occur due to delay in the onset of the first daily dose of levodopa can be due to gastrointestinal (GI) problems, which may themselves go unrecognised, and are known to be common across all stages of PD. EMO periods can be easily managed with therapeutic options that bypass the GI route,such as transdermal rotigotine, but more effectively with subcutaneous apomorphine injection. (2,3)
PD patients treated with oral levodopa gradually start to experience OFF periods where the administered dose does not adequately control their motor symptoms for the entire period of time before the next dose is taken. (4,5) Oral levodopa is considered as the best therapy for the initial management of motor symptoms in PD, however it is recognised that over time, and sometimes seen within two years of starting oral levodopa, the initial long-duration response becomes progressively shorter, leading to increasingly frequent and longer OFF periods. In addition, when a dose of oral levodopa is administered, there may be a delay in the onset of clinical effect – delayed ‘ON’ – which can contribute to an increase in OFF period duration.(5)
The clinical effect of oral levodopa relies on it being emptied from the stomach effectively and then reaching the small intestine where it is absorbed. Therefore, any delay in gastric emptying will impair delivery of levodopa to the small intestine and result in a delayed onset of its clinical effect to relieve motor symptoms.GI dysfunction is common in PD patients and includes symptoms such as poor control of salivation, dysphagia, delayed emptying of the stomach and constipation.6 Delayed emptying of the stomach, also known as gastroparesis, is frequently found in both early and advanced PD, and may even be present before motor symptoms are apparent, but often goes unrecognised.(7) Further studies have confirmed that impaired gastric emptying can alter the pharmacokinetics of an oral levodopa dose and is likely to be a causative factor underlying the delayed onset of effect in PD patients and also dose failure.(8,9)
EMO periods due to delay in the onset of the first daily dose of levodopa have been reported in up to 50% of patients who have been receiving treatment for several years.(10-12) In addition, a recent international, multicentre study has shown that EMO periods not only result in impaired motor function in PD patients but also impact a range of non-motor functions as well, including urinary urgency, anxiety, dribbling of saliva, pain and low mood.(13) Unsurprisingly, EMO periods have been reported to have a significant impact on the quality of life (QoL) of PD patients and impact on their independence and ability to get out of bed and go to the toilet, so it is important that they are recognised promptly and managed effectively.(14)
To avoid the problems associated with delayed gastric emptying, treatment strategies that employ non-oral medications which bypass the GI tract have therefore been investigated with considerable success. Apomorphine is a potent dopamine agonist that can be administered subcutaneously,thereby avoiding the GI route, and has been shown in previous clinical studies to provide fast (within 4–12 minutes) and consistent improvement in motor symptoms of PD.(12,15) More recently, interim results from the ongoing Phase IV, multicentre, open-label study – AM-IMPAKT:Apokyn for Motor IMProvement of Morning Akinesia Trial – have demonstrated that intermittent subcutaneous apomorphine injection (APO-go PEN) can provide rapid and reliable improvement in ‘time to turn ON’ (TTO) in PD patients who are experiencing EMO.(3) The study includes PD patients from 12 centres across the USA and is examining the change from baseline in average daily TTO, recorded in each subject’s diary, when they replace their usual morning dose of levodopa with subcutaneous apomorphine injection. Analysis of data for the first 50 patients found that apomorphine injection resulted in a significant improvement in TTO with an average reduction of 37 minutes compared with levodopa treatment (p<0.0001), and also reduced the number of dose failures. Overall, 95% of patients achieved a significant reduction in TTO. Apomorphine injection was well tolerated and in addition to the motor benefits there were also improvements in measures of QoL.
Apomorphine is available as an easy-to-use pen formulation for intermittent subcutaneous injection (APO-go PEN) that provides patients with a convenient way to relieve motor symptoms that occur during EMO periods, restoring them to the ON state quickly and enabling them to continue with their daily activities.
- Rizos A, Kessel B, Martinez-Martin P, Odin P, Antonini A, et al. (2013) Early morning off periods in Parkinson’s disease: Characterisation of non motor patterns and treatment effect: An international study. 9th International Congress on Mental Dysfunction and other Non-Motor Features in Parkinson’s Disease and Related Disorders. Seoul, Korea.
- Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, et al. (2011) Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord 26: 90-99.
- Isaacson S (2014) Apomorphine penject – emerging evidence and treatment strategies for delayed on and off periods in Parkinson’s disease. European Medical Journal Neurology 1: 27-35.
- Marsden CD, Parkes JD (1976) “On-off” effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet 1: 292-296.
- Melamed E, Bitton V, Zelig O (1986) Delayed onset of responses to single doses of L-dopa in parkinsonian fluctuators on long-term L-dopa therapy. | Clin Neuropharmacol 9: 182-188.
- Pfeiffer RF (2003) Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2: 107-116.
- Tanaka Y, Kato T, Nishida H, Yamada M, Koumura A, et al. (2011) Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson’s disease? An analysis using the 13C-acetate breath test. J Neurol 258: 421-426.
- Doi H, Sakakibara R, Sato M, Masaka T, Kishi M, et al. (2012) Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease. J Neurol Sci 319: 86-88.
- Chana P, Kuntsmann C, Reyes-Parada M, Saez-Briones P (2004) 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 75: 1782-1783.
- Stocchi F, Jenner P, Obeso JA (2010) When do levodopa motor fluctuations first appear in Parkinson’s disease? Eur Neurol 63: 257-266.
- Parkinson Study Group (2000) Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 284: 1931-1938.
- Dewey RB, Jr., Hutton JT, LeWitt PA, Factor SA (2001) A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol 58: 1385-1392.
- Rizos A, Martinez-Martin P, Odin P, Antonini A, Kessel B, et al. (2014) Characterizing motor and non-motor aspects of early-morning off periods in Parkinson’s disease: an international multicenter study. Parkinsonism Relat Disord 20: 1231-1235.
- Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F (2005) Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 20: 224-230.
- Pfeiffer RF, Gutmann L, Hull KL, Jr., Bottini PB, Sherry JH (2007) Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinsonism Relat Disord 13: 93-100.