Drugs for Parkinson's disease reviewed

Background

Idiopathic Parkinson's disease is a progressive neurodegenerative disorder that affects around 165/100 000 population in the UK.2 Prevalence increases with age, so that the disease affects around 1 in 200 people aged over 65 years . The main clinical features are tremor at rest, rigidity, hypokinesia, bradykinesia and postural instability, with difficulty in stopping, starting and turning when walking. None of these are specific to Parkinson's disease, and so the diagnosis is not always straightforward.3 To improve accuracy all patients should be referred for diagnosis to a neurologist or other specialist with specific experience in movement disorders.

The newly diagnosed patient

In the early stages of Parkinson's disease no treatment may be needed other than an explanation of the nature of the condition and its prognosis, together with advice about coping with symptoms and maintaining a good level of general fitness. Information on these can be obtained from the Parkinson's Disease Society.*

* Parkinson's Disease Society, 22 Upper Woburn Place, London, WC1H ORA. Tel: 0171 383 3513

Ultimately the patient will need to take levodopa with or without a dopamine receptor stimulant. However, because levodopa can cause unwanted effects, which in some patients are as troublesome as Parkinson's disease itself, and because benefit declines as treatment continues, there is a trend to delay starting the drugs until symptoms interfere with everyday life. Accordingly, in the early stages of the disease and before beginning definitive treatment, alternative drugs such as antimuscarinics, selegiline and amantadine are often tried. Candidates for these alternatives would be patients who have symptoms, such as tremor, that are becoming troublesome but in whom overall disability is mild.

Antimuscarinic drugs (e.g. benzhexol, orphenadrine) block cholinergic receptors in the striatum and reduce the relative excess of cholinergic activity that accompanies dopamine deficiency. They are particularly useful in reversing tremor, the presenting feature in 80% of patients.4 Common unwanted effects include dry mouth (which may be an advantage in those who salivate excessively), constipation and hesitancy; confusion and hallucinations limit their use in older people. If an antimuscarinic drug is to be stopped this should be done slowly because abrupt withdrawal can worsen symptoms.

Amantadine can help some patients with Parkinson's disease, improving bradykinesia, tremor and rigidity, but effects overall are modest.4 It is thought to combine the properties of an antimuscarinic drug and a weak dopamine agonist; recent research suggests that it might also work as a glutamate antagonist.5

Selegiline selectively inhibits monoamine oxidase B, so reducing the breakdown of dopamine and thus increasing the amount available at the synaptic cleft. Its effects in Parkinson's disease are not clear. While some use it in an attempt to delay the need for levodopa, several of our consultants feel it has little clinical value. Early research suggested it was neuroprotective, with the results of a study of 800 patients indicating that selegiline monotherapy could delay the need for levodopa by an average of about 9 months by reducing the rate of progression of the underlying disease.6 However, a more recent study in 782 patients failed to confirm that the drug had such neuroprotective properties.7

When definitive treatment is required

Levodopa remains central to the drug treatment of Parkinson's disease, but its introduction is usually delayed until the patient's mobility is impaired to the point of causing difficulties in the home or at work. It is given in combination with a peripheral dopa-decarboxylase inhibitor such as carbidopa (in co-careldopa; Sinemet) or benserazide (in co-beneldopa; Madopar), which prevent the breakdown of levodopa to dopamine outside the brain, thereby reducing peripheral unwanted effects. The inhibitor also ensures that a relatively large amount of an oral dose of levodopa reaches the striatum unchanged. Once in the striatum, levodopa is converted by decarboxylation into dopamine. To minimise unwanted effects such as nausea, vomiting and postural hypotension the drug should be started at a low dose of about 125-500mg daily in divided doses taken after meals. The exact dose depends on the patient's age, sex, and body weight. The dose is then slowly titrated upwards according to the patient's response. Despite this titration some patients still experience nausea and vomiting, which can be reduced by giving domperidone. Domperidone does not cross the blood-brain barrier and so does not cause worsening of parkinsonism. Levodopa titration is usually continued over 3-5 years as the condition deteriorates; disability tends to return to pretreatment levels after about 4-5 years.7

Response fluctuations

After about 8 years of treatment with levodopa approximately half of all patients (and almost all of those under 40 years) develop choreoathetoid dyskinesia plus end-of-dose deterioration.8^,9 Some patients experience fixed dystonic spasms in the hands or legs, which may be painful and debilitating. These often occur in the early morning before the drug is taken or when the effect of the daytime dose is wearing off.

The traditional approach to response fluctuations is to increase the frequency of administration of levodopa while keeping the overall dose steady: 200mg of levodopa three times daily would, for example, be converted to 100mg six times daily. This manoeuvre reduces end-of-dose deterioration and diminishes the likelihood of the patient developing the dyskinesias that occur with high 'peak' doses. Care must be taken, however, to avoid the individual dose falling below the threshold for a clinical response. These fluctuations, which are associated with changes in drug levels, are distinct from the 'on-off' (yo-yo) phenomenon in which the patient switches, over minutes, between mobility and immobility and which is commonly unaffected by manipulation of dose.

Modified-release levodopa preparations slow the absorption of levodopa and produce a prolonged and steady plasma concentration of the drug. Modified-release preparations of both co-careldopa (Sinemet) and co-beneldopa (Madopar) are marketed; co-careldopa delays the absorption of levodopa marginally longer, otherwise there is nothing to choose between them.10^,11 Modified-release formulations reduce 'wearing off' time, and for this reason many patients prefer them to standard preparations.12 However, in practice, when symptoms become more severe the conventional formulations still have the advantage that they offer a more predictable time course. This has led to a combined approach using both standard and modified-release preparations taken several (3 or 4) times a day. The longer action of modified-release formulations can also reduce severe nocturnal akinesia, which causes difficulties such as turning in bed.13 Whether early use of frequent dosing reduces the long-term complications of therapy remains unknown. There is some evidence that modified-release preparations used from the outset of treatment may prevent, delay or reduce motor response fluctuations and possibly dyskinesias,14 but there are as yet no results available from clinical trials designed to answer this question. Modified-release preparations are more costly than standard levodopa.

Dopamine agonists act directly on post-synaptic dopaminergic receptors and so, unlike levodopa, do not need to be converted in the brain to active compounds. One group of agonists, the ergot derivatives bromocriptine, lysuride and pergolide, are sometimes useful when levodopa alone is no longer adequate or when it cannot be tolerated. Pergolide stimulates both D₁ and D₂ dopamine receptors, whereas bromocriptine and lysuride preferentially stimulate D₂ receptors.15 The few comparisons made of bromocriptine, pergolide and lysuride have involved only small numbers of patients.15^,16 Their efficacy appears similar, but pergolide has the advantage of a longer half-life.15^,16 All three agonists can cause peripheral dopaminergic unwanted effects, such as nausea and vomiting, so should be introduced gradually and preferably with domperidone cover. Titration of the agonist dose over 2-3 months may allow a reduction in levodopa dose. In this way 'on' time can be increased with less dyskinesia and dystonia. Whether a dopamine agonist given early in the disease can delay fluctuations in symptom relief, particularly in younger patients, is not known.17

▼Apomorphine is a potent D₁ and D₂ dopamine agonist unrelated to ergot and usually given subcutaneously. It commonly causes nausea and vomiting and should be given with domperidone, which should be started three days before treatment and continued at least until tolerance develops. Either the patient or carer can give apomorphine by intermittent injection when an 'off' period occurs. Within 10-15 minutes this can switch the patient back to an 'on' period lasting about 45 minutes, during which time a dose of oral medication should have taken effect. Up to ten injections may be needed each day, but most patients use about five.18 Continuous subcutaneous infusion avoids the need for repeated injections and can sometimes virtually eliminate 'off' periods. If this approach is to be used, patients and carers need to know how to set up the infusion pump; once set up, the infusion should last about 12 hours. The dose needed depends on the dose of other dopaminomimetics being given.18 Both intermittent subcutaneous injection and subcutaneous infusion are generally well tolerated. However, the injection site should be changed every 12 hours as skin discoloration and nodules can occur.18 Rarely patients using injections develop autoimmune haemolytic anaemia and so patients on apomorphine should have 6 monthly full blood counts.18 Clinical benefits must be weighed against the unwanted effects, the cost of admitting the patient to hospital to establish the technique and the cost of purchasing the infusion pump and infusion lines. Use is best restricted to patients treated by departments with a special interest in Parkinson's disease and, optimally, supported by a nurse back-up for home visits for patients experiencing difficulties.

Treating the severely disabled

Patients severely disabled with Parkinson's disease will usually be taking levodopa many times a day, with or without a dopamine agonist and, in some, selegiline. It is sometimes possible to continue antimuscarinics, but often they have to be stopped because of confusion or hallucinations. At this stage there is little more antiparkinsonian drugs can offer.

Adjunctive treatment

The role of physiotherapy, occupational therapy, and speech therapy remain unclear.19 Trials of physiotherapy have been small, open and often not randomised; and difficulties with follow-up have been common. The balance of evidence suggests that physiotherapy can help some patients but has to be continued if benefit is to last.

Speech may be impaired in Parkinson's disease in several ways. It may become quiet and monotonous, with loss of normal variability in pitch, emphasis and rhythm and disturbances in the rate of speaking. Studies of speech therapy for such patients have been few and small. Significant but unsustained benefit has been reported.20–22 Late in Parkinson's disease patients may have difficulty with swallowing; limited work suggests that the speech therapist or dietician may help.23

Associated conditions

Depression occurs in 40 to 50% of patients at some point in their illness,24 and usually this can be relieved with a tricyclic antidepressant. The improvement seems to be independent of any dopaminergic or anticholinergic effect.24 Very rarely electroconvulsive therapy may be necessary to relieve depression, and in a few patients as depression has improved there has been an associated improvement in parkinsonian symptoms.24

The reported prevalence of dementia in patients with Parkinson's disease varies from 20 to 77% depending on case selection and diagnostic criteria.24 All dopaminergic agents can exacerbate confusion and visual and auditory hallucinations. In the later stages of the disease, many patients tread a tightrope between unwanted psychiatric effects and immobility.24

Organisation of services and support

Many neurology departments in the UK now run specialised Parkinson's disease clinics supported by specialist nurses who also see patients at home and in the community. These arrangements provide expert guidance on the management of the condition as a whole. Expansion of such schemes may help some patients and their carers, but studies are needed to show that the cost of the schemes is justified by improved outcomes.25

Support for the carer is essential. Provision of respite care for the patient together with specialised holiday facilities, financial support and advice on arranging institutional care helps carers to look after patients at home, but current arrangements are inadequate. This is an aspect of care that is often underestimated by the medical profession and yet for Parkinson's disease, like many other conditions, carers are crucial to treatment, particularly as the disease advances.

Conclusion

In the initial stages of Parkinson's disease it is best to provide counselling and advice, delaying drug therapy for as long as possible. Younger patients with tremor may be helped with antimuscarinics, which should be started if the tremor is becoming troublesome. The value of selegiline at this or any stage of the disease is not clear. Amantadine makes little overall impact on treatment.

When patients develop significant functional impairment, standard levodopa (with a peripheral dopa-decarboxylase inhibitor) should be started in low doses to minimise unwanted effects. A gradual increase in dose is required over the following years. When dyskinesia and end-of-dose deterioration develop, standard levodopa should be given with increasing frequency through the 24 hours. A modified-release preparation, used either alone or in combination with standard levodopa, offers an alternative approach. Yet another approach is to add a dopamine agonist such as pergolide (with domperidone), cautiously titrating the dose against the patient's response. For patients with severe fluctuations, subcutaneous apomorphine by intermittent injections or continuous infusions may help, but this must be supervised by units with expertise in the management of Parkinson's disease.