Continuous dopaminergic stimulation (CDS) and Parkinson's
In a healthy brain, brain cells release dopamine relatively constantly which ensures adequate control of movement and behaviour.
In people with Parkinson’s, dopaminergic medications are prescribed to make up for insufficient dopamine production due to loss of dopamine-producing neurons in a specific brain region called the substantia nigra. Levodopa is prescribed because it is transported to the brain where it is converted to dopamine. This re-establishes, at least for the first few years, relative normality. However, this intermittent or pulsatile form of stimulation does not mimic the brain’s natural, continuous production of dopamine. Also absorption of oral medication is affected by the natural emptying of the stomach. As the period over which a dose of medication remains effective shortens as Parkinson’s progresses, you therefore need to take frequent doses to maintain good levels of dopamine.
It is widely agreed that taking intermittent doses of oral levodopa in the long-term increases the risk of developing dyskinesia (movement that you cannot control) and fluctuations in movement. These movement changes arise as a result of the variations in brain dopamine levels. Although the precise mechanisms underlying the emergence of motor complications are debated, it is generally accepted that:
- dyskinesias appear almost exclusively if you take oral levodopa
- there is a relationship between dyskinesia and your total daily dose of levodopa
- there is a time delay between when you start levodopa treatment and the emergence of motor complications. This is probably related to how many dopamine-producing neurons you have lost.
The theory that pulsatile (intermittent) stimulation causes motor complications has led to the development of CDS treatments. These aim to imitate the brain's normal continuous pattern of stimulating the dopamine-producing neurons, thus maintaining more constant levels of dopamine. This continuous rather than intermittent pattern seems to prevent or delay the onset of motor symptoms, or reduce their intensity.
It is not so much the actual medication but the method of delivery - continuous rather than pulsatile - that seems to be crucial.
Research into CDS is ongoing but studies1,2 have shown that:
- CDS reduces the risk of motor complications when compared with levodopa or other short-acting dopamine agonists
- CDS may delay the emergence of motor complications or dyskinesias in people who are newly diagnosed with Parkinson’s (as seen in the ADAGIO trial into the effects of the once daily CDS medication rasagiline3).
Also, as CDS aims to provide continuous delivery over a 24 hour period, it can help you overcome sleep disturbances you may experience when your oral medication wears off during the night. Studies4 suggests that CDS can lead to a better night’s sleep, reduced daytime sleepiness and possibly reduced risk of behavioural disturbances5.
Infusion treatments can be cumbersome. Currently, the number of people using CDS is still limited due to the complexity of implanting devices and managing the administration of medications. However, technical advances are making this easier and complications less likely.
- Nutt J G, Obeso J A, Stocchi F, “Continuous dopamine-receptor stimulation in advanced Parkinson’s disease”, Trends Neurosci(2000); 23:pp. S109–115 - view abstract
- Olanow W, Schapira A H, Rascol O, “Continuous dopamine-receptor stimulation in early Parkinson’s disease”, Trends Neurosci(2000); 23:pp. S117–126 - view abstract
- A double-blind, delayed-start trial of rasagiline in Parkinson's disease - Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed E, Poewe W, Stocchi F, Tolosa E; ADAGIO Study Investigators. N Engl J Med. 2009 Sep 24;361(13):1268-78 - view abstract
- Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease - D. Nyholm, A. I.M. Nilsson Remahl, N. Dizdar, R. Constantinescu, B. Holmberg, R. Jansson, S-M. Aquilonius, H. Askmark Neurology, 2010 Jan 23; Vol 68 (4) 272-276 - view abstract
- Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life - Honig H, Antonini A, Martinez-Martin P, Forgacs I, Faye GC, Fox T, Fox K, Mancini F, Canesi M, Odin P, Chaudhuri KR. Mov Disord. 2009 Jul30;24 (10):1468-74 - view abstract
The ultimate goal of CDS is the development of a long-acting oral formulation of levodopa which is able to provide a more constant delivery in an easy to use way.
Levodopa/carbidopa and apomorphine infusions together with deep brain stimulation (DBS) are the most widely used CDS treatments. Although they are available in many countries, their use is still somewhat limited due to the cost and complexity of treatment and the selection criteria for suitable candidates.
Subcutaneous apomorphine infusion
A continuous supply of the dopamine agonist apomorphine can be administered via a portable, battery powered syringe pump which injects the medication under your skin, usually into your outer thigh or into your stomach just below your navel. Various studies have shown that this can reduce ‘off’ time by between 50% - 80% and it can also minimise dyskinesias.
An important advantage of apomorphine is that it acts quickly and reliably so that you can be active when you need to be and can continue with your usual activities. This can be a relief if you have extreme fluctuations in symptoms and prolonged ‘off’ periods.
Apomorphine is only helpful if you respond well to levodopa and it can cause nausea. Also, administering apomorphine intravenously can cause skin nodules and tends to be irritating to veins and soft tissues, so it may not be suitable for long term use.
For more information see Apomorphine.
Continuous levodopa/carbidopa infusion
Levodopa is rapidly and fully absorbed from the small intestine, so when taken orally, emptying of the stomach can interfere with its effectiveness. A levodopa/carbidopa gel infusion was therefore developed to deliver levodopa directly into the duodenum (small intestine) so that absorption would not be affected by gastric emptying. This allows a continuous and even flow of medication that can be adjusted over time according to your needs. It is administered by a small portable pump connected to a narrow tube which is surgically inserted into your duodenum so that it is permanently in place.
In clinical trials, levodopa/carbidopa infusion has been shown to be safe and effective, reducing or eliminating many symptoms and so improving quality of life1,2
However, some practical difficulties can arise, in particular the tube becoming entangled or dislodged, abdominal pain or infection, problems with surgery or problems with the pump.
Levodopa/carbidopa infusion may be a good alternative for people who are not suitable for brain surgery, particularly as treatment can stop at any time and the pump and tube can be removed. Selecting suitable candidates, together with good education for users, carers and healthcare professionals, are key to successful treatment.
For more information see Duodopa.
Deep brain stimulation (DBS)
DBS is another form of continuous stimulation, this time using electrical pulses to stimulate the brain. DBS uses neurostimulators to deliver electrical stimulation to precisely targeted areas through surgically implanted electrodes, similar to cardiac pacemakers, on each side of your brain. Stimulation appears to block the signals that cause disabling motor symptoms and so helps provide greater control over movement. You should remember that generally DBS does not provide benefit to symptoms that are not improved by levodopa.
Although DBS can be very beneficial, it is not suitable for everyone.
For more information see Deep brain stimulation (DBS).
Other prolonged release treatments
There are other treatments that have a prolonged release mechanism to work effectively over a 24 hour period but the medication must then be taken again; they are not continuous in the same way as apomorpine and levodopa/carbidopa infusion or DBS. These treatments are however longer acting than many Parkinson’s medications and can help provide more stable levels of dopamine so that your motor symptoms are better controlled.
Rotigotine transdermal patches - Rotigotine transdermal patches contain a carrier that helps the dopamine agonist rotigotine penetrate the skin which provides sustained levels over 24 hours. These patches are used at any stage of Parkinson’s and have been found to be fairly well tolerated and effective 4,5. This form of treatment may be helpful if you have trouble swallowing. It also has the advantage of absorption not being affected by food intake.
The patch must be placed on a different part of the body each day and must not be placed in one position more than once every two weeks.
Click here for more information on rotigotine (Neupro®).
Ropinirole XL and Pramipexole ER Once daily - Both ropinirole and pramipexole are available as once daily formulations. These tablets provide similar benefit as immediate release pills, but their extended release action means you do not have to take regular doses throughout the day.
Click here for more information on ropinirole and pramipexole.
Am I suitable for CDS treatment?
Not everyone is suited to all available CDS treatments. The following broad suitability criteria may be a useful guide but you must discuss options with your doctor before making any decision regarding CDS treatment:
- apomorphine or levodopa/carbidopa infusions and DBS are generally suitable for people who are young, have troublesome motor complications that respond or have previously responded well to levodopa, and have no dementia
- DBS is suited to those with tremorthat cannot be adequately controlled by medication
- DBS is not suitable for anyone over the age of 75, those with significant cognitive difficulties or severe depression, or those who cannot undergo surgery
- levodopa/carbidopa infusion is not suitable for anyone who cannot undergo abdominal surgery
- apomorphine may not be appropriate for anyone who experiences significant psychiatric symptoms and has not tolerated other dopamine agonists in the past.
- Oral and infusion levodopa-based strategies for managing motor complications in patients with Parkinson's disease - Antonini A, Chaudhuri KR, Martinez-Martin P, Odin P CNS Drugs: 2010 Feb 01; Vol 24 (2) 119-129 - view abstract
- Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease - D. Nyholm, A. I.M. Nilsson Remahl, N. Dizdar, R. Constantinescu, B. Holmberg, R. Jansson, S-M. Aquilonius, H. Askmark Neurology, 2005 Jan 23; Vol 64 (2) 216-223 - view abstract
- Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease - R. L. Watts, J. Jankovic, C. Waters, A. Rajput, B. Boroojerdi, J. Rao Neurology, 2007 Jan 23; Vol 68 (4) 272-276 - view abstract
- The Rotigotine Transdermal Patch May Provide Continuous Dopaminergic Stimulation in Early-Stage Parkinson’s Disease - D Grosset http://www.acnr.co.uk/pdfs/volume6issue2/v6i2drugs.pdf - view PDF.