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CLINICAL REVIEW: The Treatment of Parkinson's Disease

Posted on: Tuesday, 15 February 2005, 03:00 CST

The essentials

* Current drug treatments do not alter disease progression.

* Levodopa is effective for symptom control, with fewer side- effects.

* Dopamine agonists cause less dyskinesia, but are less effective.

* Selegiline is an effective treatment for early Parkinson's disease.

* Depression is common in Parkinson's, but is difficult to treat.

1. Which treatment and when to use it

The treatment of Parkinson's disease (PD) is complex and potentially confusing. There are several options in each drug class, and an increasing variety of formulations and complicated dose titration regimens. Ideally patients should be seen by those with a special interest in PD (usually consultants in medicine for the elderly or neurology, or GPs with a special interest). GPs also benefit increasingly from specialist nurse input.

Therapy is tailored to the individual, taking account of co- morbidity and quality of life. This overview of current trends in drug therapy of PD will guide GPs, who retain a central gate- keeping and co-ordinating role with the PD patient.

When to start treatment

Management remains symptomatic, because current evidence does not provide any certainty that disease progression is slowed by treatment.

Motor complications do not develop for several years, so therapy is only started once function is impaired. Discussion with the patient is required, and the decision to start treatment can be difficult.

The PD Life Study found poorer quality of life in patients who delay starting therapy, but longterm follow-up is needed to determine if this problem is compensated by fewer motor complications. In clinical trials, starting therapy is based on deteriorating disease scores (the Unified Parkinson Disease Rating Scale) or quality of life questions based on functional ability at work, home and socially.

Coming to a joint decision on when to start drug therapy should help compliance in early disease.

Which treatment to use

The choice of optimum drug class for first-line therapy in PD is debatable, and the largest ever PD drug trial (PD MED) is still ongoing and is addressing this issue. PD MED is a large randomised assessment of the relative cost-effectiveness of classes of drugs for PD. Previous comparative studies included too few patients and had inadequately short follow-up.

The main choices are between levodopa preparations with or without catechol-O-methyltransferase (COMT) inhibitors, dopamine agonists and monoamine oxidase B inhibitors.

Key points

* Treatment is only started once function is impaired.

* Discussing treatment options with the patient will help compliance in early disease.

* The choice of optimum drug class forfirst-line therapy in PD is debatable.

* The ongoing PD MED trial is addressing the issue of which treatment is best for starting therapy.

2. The rote of tevodopa preparations

Despite many new treatment developments in PD, levodopa remains the most effective therapy in terms of symptom control and side- effects, and is therefore still the gold standard.

Levodopa formulations may be immediate release, controlled release or dispersible. The problems with levodopa stem from its short halflife of about 90 minutes.

In early PD, the patient's endogenous levodopa buffers levodopa treatment, but disease progression is associated with a wearing off effect. Ultimately there is a troublesome 'on-off' phenomena (unpredictable fluctuations between mobility and an ability to function, to being slow, stiff and stuck), and drug-induced involuntary movements (dyskinesia).

Motor complications are probably due to pulsatile exogenous dopaminergic stimulation compared to the physiological steady tonic delivery of dopamine to post-synaptic neurones.

Controlled-release preparations

Controlled-release preparations have not achieved the hoped-for smoothing of symptom control, because of variable absorption and insignificant prolongation of the effective half-life to between three and four hours.

Controlled-release levodopa is currently mainly prescribed for use overnight. This is to help those patients who experience difficulty turning in bed, and can aid mobility for those with nocturia who have to get up at night.

Adding a COMT inhibitor

Adding COMT inhibitors to levodopa preparations prolongs the half- life by 30 to 50 per cent, because they reduce levodopa breakdown.

There is a choice of two preparations, entacapone and tolcapone. Tolcapone was withdrawn from the European market because of hepatic toxicity, but is soon to be re-launched with frequent liver function test monitoring.

Stalevo is a combined product of levodopa, a decarboxylase inhibitor, and entacapone. The levodopa dose can be reduced when COMT inhibitor is added, particularly if there are symptoms of dopaminergic excess. Delayed onset diarrhoea (about six weeks after starting treatment) can occur, and almost always means that the COMT inhibitor must be stopped.

Concerns over motor complications from levodopa have increased the use of dopamine agonists or selegiline as initial therapy. However, in patients with cognitive impairment or a significant vascular history, levodopa is the treatment of first choice. Patients wanting the most effective treatment with the best early improvement may opt for levodopa as their first-line drug.

Care when prescribing

Care is especially required in prescribing levodopa, as similar- sounding branded preparations contain different doses.

For example, Half Sinemet CR contains 100mg of levodopa while Sinemet CR contains 200mg levodopa, and controlled-release preparations have only 70 per cent bioavailability compared to immediate release preparations.

Sinemet 275 contains 200mg bioavailable levodopa while Sinemet CR has approximately 140mg of bioavailable levodopa.

Prescription errors can result in under-treatment, leaving the patient slow and stiff, or overtreatment, causing symptoms of dopaminergic excess (hallucinations, confusion or involuntary movements).

Key points

* Levodopa formulations may be immediate release, controlled release ordispersible.

* Troublesome 'on-off' phenomena and drug-induced involuntary movements develop with long-term levodopa therapy.

* Adding COMT inhibitors to levodopa preparations prolongs the half-life by up to 50 percent.

* Care is especially required in prescribing ievodopa, as similar- sounding branded preparations contain different doses.

3. Using dopairine agonists

Dopamine agonists are an initial therapy choice. They are an effective treatment and can cause less long-term motor complications,in particular dyskinesia, but clinical improvement is less than with levodopa.

The two main groups of dopamine agonists are those derived from ergot compounds (bromocriptine, pergolide and cabergoline) and the nonergots (ropinirole and pramipexole). Ergot preparations are rarely associated with cardiopulmonary and retro-peritoneal fibrotic sideeffects. The Committee on Safety of Medicines has issued two recent alerts over the issue.

A recent cchocardiographic study of patients treated with pergolide (The Lancet 2004; 363: 1,179-83) found sub-clinical evidence of cardiac valvular fibrosis in about a third of patients. Changes were similar to those of the carcinoid syndrome or those taking fenfluramine or methysergide and ergotamine.

Most of the patients given an informed choice elect to switch to a non-ergot preparation.

Protective effect from non-ergots

In two separate studies, the non-ergot preparations ropinirole and pramipexole were associated with a reduced loss of striatal isotope uptake on functional imaging compared to levodopa therapy, and a neuroprotective effect was proposed. However, this did not correlate with symptom control measured with motor scores.

An alternative explanation is that differential effects of the agonist and levodopa on the regulation of the dopamine system influence the scan appearance.

At present, there is no definite evidence of neuroprotection, so prescription choice cannot be made on this basis.

Side-effects

Side-effects common to all dopamine agonists include nausea and dizziness, and these can be minimised by low starting doses and slow titration. The co-prescription of domperidone is helpful until these effects diminish.

Complex titration regimens are made easier by starter packs that are available for ropinirole and pergolide.

Pramipexole requires care as tablet strength is expressed as base or salt formulations. The salt formulations have more rounded doses (0.125mg, 0.25mg and 1mg) than the base ones (88g, 18g and 700g), but prescriptions and package labelling are generally written as base.

The sudden onset of sleep is a rare side-effect of dopamine agonists. Patients should be advised not to drive for the first few days of treatment, and if sudden onset sleep develops, driving should stop until alternative therapy is started.

Other side-effects include ankle swelling, hallucinations, confusion and, rarely, compulsive gambling.

Apomorphine

Apomorphine is a short-acting non-ergot dopamine agonist which has to be given parenterally, either by subcutaneous intermittent injections or continuous infusion during the day. Specialist supervision is required.

In patients with 'on-off' fluctuations and/or disabling dyskinesia, apomorphine may allow a reduction or even discontinuation of oral m\edication and is effective at smoothing out symptoms.

Several new dopamine formulations are under test, including the transdermal agent rotigotine, and ropinirole CR, both of which may reduce fluctuations by long duration of action.

Key points

* The two main groups of dopamine agonists are ergot compounds and the non-ergots.

* Ergot preparations are associated with cardiopulmonary and retro-peritoneal fibrotic side-effects.

* Side-effects common to all dopamine agonists include nausea and dizziness.

* Apomorphineisa non-ergot dopamine agonist and has to be given parenterally under specialist supervision.

4. Monoamine oxidase B inhibitors

Currently, selegiline is the only available monoamine oxidase B inhibitor (MAOB-I) preparation. It was initially hoped that selegiline might prove to be neuroprotective, but there is no definite evidence to support this.

Prescriptions for selegiline declined rapidly after the UK Parkinson's Disease Research Group trial reported increased mortality on selegiline, but a recent MAOB-I meta-analysis found no increase in mortality with this drug class.

The review's conclusion was that MAOB-Is reduce the disability of PD, delay the need for levodopa and reduce the incidence of motor fluctuations, and are cost-effective.

Theoretically, if selegiline is used in combination with another serotonergic agent such as an SSRI or a tricyclic antidepressant, there is a risk of inducing the serotonin syndrome. This is an acute iatrogenic drug-induced condition, characterised by a triad of cognitive behavioural changes, autonomie instability and neuromuscular excitability. The syndrome is caused by overstimulation of 5-hydroxytryptamine receptors. In practice the risk is extremely low, and in one major study only 11 out of 4,568 depressed Parkinson's disease patients already on selegiline and then treated with an SSRI showed signs of a serotonin interaction.

Amantadine is a glutamate antagonist originally developed as an antiviral agent. In practice its main use is as an anti-dyskinesia agent in advanced disease, but benefit is modest.

When to change medication

In general, when a particular class of PD drug is chosen, it is initiated at low dose with a gradual dose escalation depending on response. An adequate dose to achieve efficacy must be reached, but it is best to stick at the lowest effective dose to allow for future escalation.

As the disease progresses, the dose is increased until either the maximum recommended dose is reached, or adverse effects develop. At this stage, a different class of agent is added, again starting with a low dose escalating slowly as needed. If adverse effects are troublesome, dose reduction is required.

Key points

* It was initially hoped that selegiline might proveto be neuroprotective, but evidence is lacking.

* A recent MAOB-I meta-analysis found no increase in mortality with these agents.

* Selegiline used with an SSRI or a tricyclic antidepressant may rarely induce the serotonin syndrome.

* Treatment is increased until either the maximum recommended dose is reached, or adverse effects develop, then a different agent is added.

5. Drag response and co-morbidity

Degrees of response

The three cardinal features of idiopathicPD are tremor, rigidity and bradykinesia. Improvement in tremor occurs in about half of patients, but tremor is the most difficult symptoms of the triad to control and is almost never abolished. Half of patients have no improvement in tremor, and some patients report the tremor is worse on treatment.

About 80 per cent of patients will have improvement in muscle stiffness (rigidity) and almost all will have some improvement in bradykinesia. In clinical trials, it takes about five years to return to pre-treatment level of disability.

If there is no response, there are three main considerations: the dose may be inadequate, the diagnosis may be wrong, or the patient may not be taking their medication.

Co-morbid conditions

Depression is common in patients with PD, affecting at least a third of patients, and is a key factor in quality of life. Despite the theoretical risk of antidepressants worsening parkinsonism, they are used in practice and are effective in selected patients. A Cochrane review of SSRIs and tricyclic antidepressants found only three trials that met their criteria and these showed limited benefit over placebo, concluding that there is insufficient data on the effectiveness and safety of antidepressants in Parkinson's disease.

Cognitive impairment occurs in 10-20 per cent of PD patients. All anti-Parkinson's drugs can make confusion worse, especially the anticholinergics and dopamine agonists, which are best avoided. Small doses of levodopa can be used.

Vascular disease commonly co-exists in PD, and cerebrovascular disease may cause or contribute to the parkinsonian syndrome. Again, all anti-Parkinson's medication causes hypotension and dizziness, but levodopa is more likely to be tolerated and is the treatment of choice.

Key points

* Improvement in tremor occurs in about half of patients, and can be difficult to control.

* Some patients report tremor is worse on treatment.

* About 80 per cent of patients will have improvement in muscle stiffness.

* Cognitive impairment occurs in 10-20 per cent of PD patients and treatment may make confusion worse.

Drug treatment starts when motor function is impaired and should be discussed with the patient

Hepatic toxicity was an issue with one COMT inhibitor

Ergot drugs can cause fibrotic changes

Antidepressants can react with Parkinson's treatments

Cerebrovascular disease contributes to parkinsonism

Further resources

Further reading

Movement Disorders in Clinical Practice edited by G Sawle, published by Isis Medical Media. Parkinson's Disease in Practice by C Clarke, published by the Royal Society of Medicine Press.

Websites

See Medicine on the Web, page 41

Previously in Clinical Review

You can print an A4 copy of any Clinical Review published in the past year by logging on to GPonline.com. Recent issues have covered:

* The diagnosis of Parkinson's disease (14 Jan).

* secondary headaches (17 December).

* Primary headaches (10 December).

NEXT ISSUE: Contraception: the first request, by Anne Szarewski

Contributed by Dr Katherine Grosset, GP and hospital practitioner, and Dr Donald Grosset, consultant neurologist, both at the neurology department, Southern General Hospital, Glasgow

Copyright Haymarket Business Publications Ltd. Jan 21, 2005

Source: GP

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