Clinical update: Parkinson’s disease – There are multiple problems, which are not related to dopamine, at the end stages of Parkinson’s disease (PD) for which there are no effective treatments. Patients at the end may have memory problems, pain, depression, falls and urinary difficulties.
Though it is the easiest to manipulate, dopamine is not the only neurotransmitter that is affected in PD. Serotonin, noradrenaline, acetylcholine and other brain chemicals are also affected in the condition.
It is possible to treat the core signs and symptoms of the disease by compensating for lost dopamine. L-dopa, which is converted to dopamine in the brain, is still the ‘gold standard’ – the most effective drug for Parkinson’s. Its half-life in the blood is very short, however, and a similar short effect occurs in the brain.
Though there is a ‘levodopa honeymoon’, sooner or later two problems develop and these have been related to the ‘pulsatility’ of the treatment. One is a wearing-off effect before the next tablet is due. The other problem is dyskinesias – abnormal involuntary movements. If the pulsatility can be reduced, it may be possible to avoid, delay or reduce these complications. Hence, there are potential advantages to continuous or constant delivery of dopaminergic stimulation.
Dopamine agonists (synthetic molecules that mimic dopamine) are used to treat patients at an early stage of the condition, to delay the need for levodopa. Studies in animals and patients have shown that if dopamine agonists– which have a longer duration of action – are used as initial treatment, there are fewer involuntary movements.
Oral dopamine agonists are less pulsatile than L-dopa, though their levels still rise and fall in the blood. With a patch, the levels of the drug in the blood are almost constant over 24 hours. More recently, once-a-day oral agonists – which have improved pharmacokinetics – have been manufactured in prolonged release formulations. There have not been any direct comparison studies to show whether the superior pharmacokinetics of transdermal rotigotine convey a practical advantage over these new oral agonist formulations.
For fluctuating PD patients, the waking day can be divided into ‘on-time’ when the drug is working, and ‘off-time’. If dopamine stimulation is increased across the board, patients can be ‘on’ for longer but they are disabled by dyskinesias. Thus, on-time can be subdivided into on (with troublesome involuntary movements) and on (without troublesome involuntary movements).
The aim of the CLEOPATRA-PD (Clinical Efficacy of Pramipexole and Transdermal Rotigotine in Advanced Parkinson’s Disease) trial, reported in 2007, was to determine the efficacy and safety of transdermal rotigotine, in comparison with placebo and pramipexole treatments, in patients with advanced PD.
The study found that on-time was similarly increased when using a transdermal rotigotine (dopamine receptor agonist) patch and using the oral dopamine agonist pramipexole, both being significantly better than placebo in this regard.
One problem is that the patient is usually only treated during the day. The night can be a very difficult time – patients wake up immobile and having to go to the bathroom and they may have pain.
Smaller studies are now looking at night-time disability and the wellbeing of patients first thing in the morning. Some of these studies have reported advantages when long-acting medications are used. With an agonist taken at night or a patch that covers a 24-hour period, there should be improved night-time mobility and improved early-morning condition. Again, there is so far no direct comparison between the patch and prolonged action oral agonists in relation to their relative efficacy in treating these problems.
Unlike levodopa treatment, the dopamine agonists do not cause fluctuations and involuntary movements when given alone. Dopamine agonists (and higher doses of levodopa) do, however, increase the risk of developing impulse control disorders. An American study (Weintraub et al, 2008) shows that up to 14 per cent of patients on usual dopamine agonists can get one or other of the impulse control disorders.
We now have a better understanding of the frequency and relationship to treatment of these disorders. They may be manifested as hypersexuality, pathological gambling, compulsive shopping or singing or reckless generosity.
Prof Niall Quinn, Emeritus Professor of Clinical Neurology at University College London’s Institute of Neurology, reports a patient who gave away £150,000 under the influence of one drug. Patients on dopamine agonists, and carers, should routinely be alerted that one or more of these things is a possibility in a minority of patients, said Prof Quinn.
If they are not informed, and the risk of side-effects is well recognised, there could be potential problems for doctors should patients try to sue.
About Greg Baxter
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