Parkinson’s disease: treatment

By David Burn, FRCP, MD

The treatment of Parkinson’s disease (PD) was revolutionised by the introduction of levodopa in 1967. In the relatively short period of time that has followed, the limitations of levodopa have been recognised and an increasing number of alternative drugs have been developed in an effort to circumvent these shortcomings. Furthermore, the “therapeutic wheel” has almost turned a full circle, as neurosurgical approaches, which were largely abandoned after levodopa treatment became available, are being re-evaluated for their potential role in disease management.
This review of the treatment of PD primarily considers currently available drugs. These are symptomatic therapies, since no agent has yet been shown beyond reasonable doubt to have disease modifying, or “neuroprotectective”, properties. Finally, neurosurgical treatments and a number of potential future therapies for PD will be briefly reviewed.

The “long-term levodopa syndrome”

In 1967 Cotzias and coworkers described the efficacy and tolerability of levodopa in PD patients when the drug was started in low doses and gradually increased thereafter.¹
Unfortunately, despite dramatic initial benefits, workers quickly came to realise the limitations of levodopa treatment and to recognise a phenomenon termed in the US the “long-term levodopa syndrome”. This was described in my previous article, but, in brief, comprises a premature wearing off of the antiparkinsonian effects of levodopa and fluctuations in response. The latter can include dramatic swings between gross involuntary movements (dyskinesias) and a “frozen”, immobile state.
These problems emerge at a rate of approximately 10 per cent per year, so that, by 10 years into their illness, all PD patients can expect to be experiencing such unpredictable responses.²
Notably, younger PD patients tend to develop levodopa-induced dyskinesias and fluctuations earlier after diagnosis than older patients.³
Not surprisingly, therefore, research into the medical management of PD has focused upon the use of alternative agents to levodopa, in order to delay this long-term levodopa syndrome. It might be argued that such alternatives would be of particular importance in the younger patient, in whom life expectancy is correspondingly greater.

Early therapeutic considerations

Doctors and patients tend to have different perceptions of PD. The doctor will tend to record impairments in the clinic, while the patient is more concerned with their disability and handicap. Thus, a patient can be noted to have what appear to the doctor to be marked impairments, yet may not complain about significant disability. The converse may also be true. It follows, therefore, that, while the diagnosis of PD may be beyond reasonable doubt, not all patients necessarily require immediate treatment.
After diagnosis, an explanation of the condition, education and support are essential. If available, a PD nurse specialist is invaluable at this early stage. The Parkinson’s Disease Society (PDS) also produces an excellent range of literature to help the newly-diagnosed patient come to terms with their condition. In accordance with advice given by the PDS itself, patients who drive are recommended to inform their insurance company and the DVLA.
When treatment becomes necessary, it is impossible to generalise about which drug should be commenced. A number of factors, including age, severity and type of disease (tremor-dominant versus bradykinesia-dominant), and co-morbidity, need to be taken into account. Current trends have shifted towards either late administration of levodopa (provided that alternative treatments can give adequate symptomatic control) or the use of combination therapies, in an effort to reduce the longer-term problems associated with levodopa. However, the evidence that such strategies truly benefit the patient remains relatively weak and this continues to be an area of debate.^4,5

Antiparkinsonian drugs

Immediate-release levodopa
Despite the ongoing discussions regarding early or late levodopa therapy, there is no doubt that this drug remains the most effective oral, symptomatic treatment for PD.
It is administered with a peripheral dopa-decarboxylase inhibitor (DDI) as carbidopa plus levodopa (co-careldopa [Sinemet]) or benserazide plus levodopa (co-beneldopa [Madopar]). The DDI prevents the formation of dopamine peripherally, and thereby allows a lower dose of levodopa to be administered. The levodopa in these preparations crosses the blood-brain barrier, where it is converted by endogenous aromatic amino acid decarboxylase to dopamine. It is then stored in surviving nigrostriatal terminals. Immediate-release levodopa is usually commenced at a dose of 50mg per day, increasing every three to four days until a dose of 50mg three times daily is reached. Patients should be instructed, in the early stage of their illness, to take the drug with food to minimise nausea. Paradoxically, in the more advanced stages of PD, it may be beneficial for the patient to take their levodopa preparation 30 minutes or so before food, since the protein load in the diet can interfere with the absorption of the drug at this time. The competition from neutral amino acids in the dietary protein with the levodopa may be sufficient to reduce levodopa plasma levels critically. In the advanced stages of PD, the levodopa dose-response curve becomes a sigmoid function and this reduction in the plasma level of the drug may lead to failure to produce a motor response (a “no on” effect).
If there is little, or no, response to 50mg three times daily, the unit dose may be doubled to 100mg. Should the patient’s levodopa dose escalate to 600mg per day with no significant response, the diagnosis of PD should be questioned.
Levodopa, commenced in the above way, is usually well tolerated. Nausea, vomiting and orthostatic hypotension are the most commonly encountered side effects. These adverse events may be circumvented by increasing the levodopa dose more gradually, or by co-prescribing domperidone 10 or 20mg three times daily. Later in the course of the illness, and in common with all antiparkinsonian drugs, levodopa may cause vivid dreams, nightmares and even a toxic confusional state.
Clinically relevant drug interactions with levodopa include hypertensive crises with monoamine oxidase type A inhibitors (MAOI-A). It is, therefore, advised that levodopa be avoided for at least two weeks after stopping an MAOI-A. In addition, levodopa can enhance the hypotensive effects of antihypertensive agents and antagonise the action of antipsychotics. The absorption of levodopa may be reduced by the concomitant administration of oral iron preparations.

Controlled-release levodopa preparations
Both Sinemet and Madopar are available as controlled release (CR) preparations. The nomenclature for Sinemet CR is particularly confusing, as the drug is marketed as Sinemet CR (carbidopa/levodopa 50/200) and also as Half Sinemet CR (carbidopa/levodopa 25/100). Trying to prescribe Half Sinemet CR unambiguously can be difficult: if the instruction is misinterpreted and a tablet of Sinemet CR is halved, the slow-release mechanism is disrupted.
The levodopa in CR preparations has approximately 60-70 per cent bioavailability. This is less than the 90-100 per cent seen with immediate-release formulations. In contrast with immediate-release levodopa, the bioavailability from CR preparations is increased in the presence of food.⁶

Two large studies have now been published comparing the use of immediate-release and CR preparations in early PD. No benefit for CR over immediate-release levodopa was demonstrated in terms of dyskinesias and response fluctuation frequency at five years.^7,8
However, CR preparations, by virtue of their prolonged response duration (two to four hours for CR versus one to three hours for immediate-release), may be of help in terms of simplifying drug regimens and in relieving nocturnal akinesia (freezing). It is often useful to prescribe a CR preparation, with immediate-release levodopa given during the day to relieve end-of-dose deterioration.
Changing a patient from all immediate-release to all CR levodopa is often poorly tolerated, as the CR levodopa has a longer latency than immediate-release levodopa to turn the patient “on” (typically 60 to 90 versus 30 to 50 minutes). In addition, the patient’s perception is that the quality of their “on” period is poorer after such a change. CR preparations should not be prescribed more than four times a day (I usually restrict patients to three doses), as the levodopa may build up unpredictably, causing increased dyskinesias and confusion.

Dopamine agonists (oral)
In 1973, bromocriptine was found to cause prolonged dopamine receptor stimulation and the following year beneficial effects of bromocriptine in PD were reported.⁹
Theoretically, dopamine agonists, which stimulate dopamine receptors both post- and pre-synaptically, would seem to be an attractive therapeutic option in PD, since they may bypass the degenerating nigrostriatal dopaminergic neurones. Unfortunately, experience to date with these drugs has generally revealed them to be less potent than levodopa and to be less well tolerated. The dopamine agonists differ in their affinity for a number of receptors, including the dopamine receptor family (see Table 1). It is not yet known whether these differences are clinically significant.
Dopamine agonists may be used as initial treatment or as adjunctive therapy (so-called “levodopa sparing”) in the management of PD. Of those available, only bromocriptine and ropinirole are currently licensed for early treatment of PD in the UK. Recent studies have indicated that ropinirole is as effective as levodopa in early PD and that the drug has some advantages over bromocriptine (although it is also more expensive).¹⁰
All dopamine agonists may be used as add-on therapy to levodopa in the later stages of the disease, when motor control has become sub-optimal. This may necessitate a concomitant reduction in levodopa dosage to avoid excessive dopaminergic side effects. There have been very few comparative studies performed between the dopamine agonists, so it is not possible to be definitive as to which drug should be recommended. In practice, it is often worth changing from one agonist to another if side effects are a problem, since there is variability in a given patient’s tolerance to the different drugs.

The principal side effects of the dopamine agonists are nausea and vomiting, postural hypotension, hallucinations and confusion, and exacerbation of dyskinesias. Ergot derivatives (see Table 1) may cause pleuropulmonary fibrosis. This has been estimated to occur in 2-6 per cent of patients on long-term bromocriptine treatment. In addition, a recent report of this complication occurring after an average of two years treatment in three patients taking pergolide highlighted the variable, and occasionally life-threatening, manifestations of pleuropulmonary fibrosis.¹¹
Yearly monitoring with chest x-ray and erythrocyte sedimentation rate (ESR) has been suggested for patients taking ergot derivative agonists, although the utility and cost-effectiveness of this recommendation have not been established. There is also an increased risk of toxicity when erythromycin is co-prescribed with a dopamine agonist.

Both ropinirole and pramipexole have recently been implicated in causing sleep attacks, with sudden onset of drowsiness leading to driving accidents in some cases.¹²
The term “sleep attack” is almost certainly a misnomer as studies have indicated that there is a prodromal period of drowsiness prior to falling asleep. However, patients are subsequently unable to recall this “warning” period of drowsiness. Excessive sleepiness attributable to antiparkinsonian drugs is certainly not a new phenomenon, and has previously been reported with levodopa. It is obviously essential to advise patients taking all antiparkinsonian agents, especially ropinirole and pramipexole, that they may be prone to excessive drowsiness. This may be compounded by the use of other sedative drugs and alcohol.

Dopamine agonists (parenteral)
Apomorphine remains a highly specialised, costly and almost certainly underused drug in the treatment of PD. It is the most potent dopamine agonist available and is currently administered subcutaneously either by bolus injection or by continuous subcutaneous infusion. The drug is quite acidic and is generally difficult to administer in a stable form that does not lead to irritation of skin or mucosal surfaces. Alternative methods of administration, including via transdermal and intranasal routes, are being evaluated.
The drug produces a reliable “on” effect with a short latency of action. A single bolus lasts for up to 60 minutes, depending upon the dose given. Recent reports suggest that continuous subcutaneous apomorphine may significantly improve dyskinesias in advanced PD, as well as lessening akinesia and rigidity.¹³
The reduction in dyskinesias (a so-called “chemical pallidotomy”) may take several months to become fully apparent. This may allow oral antiparkinsonian medications to be reduced.
Apomorphine may cause profound nausea, vomiting and orthostatic hypotension, which may be counteracted by pre-dosing for two to three days with 20mg of domperidone three times a day. Neuropsychiatric disturbance (probably at a lower frequency than with oral agonists) and skin reactions (including nodule formation) are other potential side effects of the drug. Apomorphine, in conjunction with levodopa, may cause a Coomb’s positive haemolytic anaemia, which is reversible. It is recommended that patients be screened prior to beginning treatment and at six monthly intervals thereafter. Establishing a patient on apomorphine is greatly helped by the supervision of a nurse specialist, if available.

Selegiline
This is a selective, irreversible inhibitor of monoamine oxidase (MAO) type B. Inhibition of this enzyme slows the breakdown of dopamine in the striatum. Some recent work has also suggested that selegiline may have an anti-apoptotic effect. (Apoptosis is a form of programmed cell death thought to be important in several neurodegenerative conditions, including PD.) Whether or not the drug has a neuroprotective effect by this or other means remains controversial.
A dose of 5 to 10mg of selegiline per day is normally prescribed. Higher doses are associated with only minimal additional inhibition of MAO-B.
Following the publication of the UK Parkinson’s Disease Research Group study in 1995, where an excess mortality in the group of patients taking selegiline was demonstrated, prescriptions for the drug in the UK (but not in the US) dropped by nearly 50 per cent.¹⁴
This study drew much criticism from some quarters, both in its design and in the analysis of the data. Nevertheless, a more recent observational study from the UK General Practice Research Database also suggested a small excess mortality in patients taking selegiline.¹⁵
The reason for this effect is uncertain, but it has been suggested that the drug should be avoided in patients with known falls, confusion and postural hypotension. The use of selegiline in younger patients with early PD, as a means of deferring levodopa treatment, still has its advocates.
The mild amphetamine-like properties of selegiline’s metabolites account for some of its side effects, which include hallucinations and confusion, particularly in moderate to advanced disease. Withdrawal of selegiline in some patients may also be associated with a significant deterioration in motor function. Selegiline is best avoided as a co-prescription with selective serotonin re-uptake inhibitors (SSRIs), since a “serotonin syndrome” that includes hypertension and neuropsychiatric features, has been reported in a small minority of cases.

Amantadine
This was introduced as an anti-parkinsonian treatment in the late 1960s. It has a number of putative mechanisms of action, including the facilitation of pre-synaptic dopamine release, blocking dopamine re-uptake, an anticholinergic effect, and also as an N-methyl-D-aspartate (NMDA) receptor antagonist. Initially employed in the early stages of PD treatment, where its effects are mild and relatively short-lived, interest has recently focused upon the use of amantadine as an anti-dyskinetic agent in advanced disease.¹⁶
The dose range for amantadine is 100 to 300mg, although the lower end of the range is more commonly used because of the risk of increased side effects at higher dosages.
Side effects of amantadine include confusion and hallucinations, peripheral oedema and livedo reticularis (reddish-blue mottling of the legs, which may be associated with chronic ulceration). There may be significant worsening of parkinsonism after the drug is withdrawn.

Anticholinergic drugs
The availability of anticholinergic drugs, such as benzhexol and orphenadrine, predated the introduction of levodopa. However, the prescription of these drugs has fallen markedly because of troublesome side effects, including cognitive impairment and frank confusional states. In selected younger patients, the anti-tremor effect of these agents may still be helpful but close monitoring is advised.

Catechol-o-methyl transferase (COMT) inhibitors
The introduction of COMT inhibitors to the market has been eventful. After a long gestation as a class of drugs, second generation inhibitors were developed in the 1980s. Unlike first generation COMT inhibitors (gallates and tropolone), these agents were shown to be potent, reversible and highly specific inhibitors of COMT. The first commercial COMT inhibitor available – tolcapone – lasted only a few months on the UK market before the EU suspended the drug in November, 1998, because of reports of fatal hepatotoxicity. However, tolcapone can still be prescribed in the US. A second COMT inhibitor, entacapone, was released shortly after tolcapone and is the only drug of this class currently available in the UK.
COMT itself is a ubiquitous enzyme, found in the gut, liver, kidney and brain, among other sites. In theory, COMT inhibition may occur both centrally (where the degradation of dopamine to homovanillic acid is inhibited) and peripherally (where conversion of levodopa to the inert 3-O-methyldopa is inhibited) to benefit the patient with PD.
In practice, both tolcapone and entacapone act primarily as peripheral COMT inhibitors.¹⁷
When entacapone is prescribed, a 200mg dose is used with each dose of levodopa administered, up to a frequency of 10 doses per day. Because of increased dyskinesias, an overall reduction of 10 to 30 per cent in the daily dose of levodopa should be anticipated. While entacapone may be given with any other antiparkinsonian drug – although caution may be needed with apomorphine – its optimal use is uncertain.
The patient with moderately advanced disease who is experiencing end-of-dose deterioration, or who is generally under-dosed, would seem to be the ideal candidate. Sadly, there are no comparative studies of entacapone versus dopamine agonists available to provide guidance as to which class of drug is best to use, and when. Other than exacerbation of dyskinesias, COMT inhibitors may cause diarrhoea (particularly tolcapone), the mechanism for which is unknown, abdominal pain, and dryness of the mouth. Urine discoloration, caused by metabolites of COMT inhibitors, is reported in approximately 8 per cent of patients.¹⁷

It is best to avoid non-selective MAO inhibitors or a daily dose of selegiline in excess of 10mg when using entacapone. In addition, it is also suggested that the use of venlafaxine and other noradrenaline re-uptake inhibitors be avoided in patients taking this drug. Entacapone may potentiate the action of apomorphine. Patients taking iron preparations should be advised to separate these from entacapone by at least two hours.

Neurosurgery for Parkinsons disease

As alluded to in the introduction, there has been a renaissance of interest in the use of neurosurgical techniques for the treatment of PD. This has resulted not only from recognition of the shortcomings of medical treatment currently available, but also from our improved understanding of basal ganglia circuitry and better neuroimaging methods. A detailed consideration of this topic is beyond the scope of this article, and the reader is referred to recent reviews.^18,19

Potential future therapies

Medical treatments under development for PD fall into three categories. First, new means of delivering existing drugs are being explored (via the transdermal route, for instance). Secondly, drugs which are active via non-dopaminergic systems are being evaluated, particularly for their potential as anti-dyskinetic agents. Finally, neuroprotective and neurotrophic agents are being considered. A number of these, including intraventricular glial-derived neurotrophic factor, have already shown promise in animal studies. Table 2 lists several drugs in these different categories at various stages of development as potential future treatments for PD.²⁰

Conclusion

The treatment of PD represents a significant challenge. Unresolved issues include determining which is the optimum agent(s) with which to initiate treatment in the newly diagnosed patient. Furthermore, while the therapeutic armoury continues to expand, direct comparison between drugs within a particular class is generally lacking and it is uncertain when one class of drug should be introduced compared with another (dopamine agonists versus COMT inhibitors, for example). In the later stages of PD, there is an urgent need for novel anti-dyskinetic agents, to allow the bradykinesia to be effectively treated by levodopa and/or similar dopaminergic preparations, without inducing severe drug-related involuntary movements. Finally, the challenge of developing an effective neuroprotective therapy for PD remains an exciting, if elusive, goal.

Dr Burn is consultant and senior lecturer in neurology at the Regional Neurosciences Centre, Newcastle General hospital

Credit for Learning: 1

This article forms the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme

The Pharmaceutical Journal Vol 264 No 7089p476-479 March 25, 2000 Continuing education