Management of Parkinson’s disease

Parkinson’s disease has a wide variety of motor and non-motor symptoms.

Treatment aims to control the patient’s symptoms by replenishing the dopaminergic system with levodopa or dopamine agonists. Monoamine oxidase B inhibitors are also effective first-line drugs.

Keeping symptoms under continual control early in the course of the disease may have beneficial effects as Parkinson’s disease progresses.

Therapy is tailored to each patient’s response to the drugs and their ability to tolerate them. Limited responses of motor and many non-motor symptoms may require the addition of other treatments.

The adverse effects of drugs used in the treatment of Parkinson’s disease are usually reversible.

Symptom fluctuations in response to regular medication are an indication for specialist referral.

Parkinson’s disease is a common neurodegenerative disorder, which particularly involves the loss of nigral dopaminergic neurons. The cardinal motor features are rigidity, bradykinesis, rest tremor and postural instability. Non-motor features are common both early and late in the disease course and include autonomic, neuropsychiatric and cognitive disturbances. Parkinson’s disease has manifestations beyond the nigrostriatal system so it is not surprising that some motor features (such as postural instability) and many non-motor features have a limited response to dopaminergic drugs.

Non-drug therapies have a significant role in the treatment of Parkinson’s disease and include counselling and education for both patients and carers. This includes providing information about which commonly prescribed drugs to avoid, for example dopamine-blocking drugs such as metoclopramide, prochlorperazine, haloperidol and risperidone. It is important to increase general fitness and well-being and maintain core balance and strength which may improve gait and postural stability. Physiotherapy with large amplitude physical training improves motor function¹ and allied health professionals can provide specific strategies to overcome disabilities such as start hesitancy, freezing of gait, festination and falls. Lee Silverman voice training is an established technique which has been proven to improve voice quality and audibility when patients adhere to the long-term strategy.² Nutrition should be considered in all stages of Parkinson’s disease.

Supportive care is vital in very advanced phases of Parkinson’s disease as drugs become poorly tolerated, motor fluctuations increase and non-levodopa responsive symptoms dominate. Counselling is part of the management of non-motor symptoms such as anxiety and depression, cognitive dysfunction and dementia.

There are no proven neuroprotective treatments for Parkinson’s disease, but drugs are effective in symptom control, particularly in the early stages of the disorder. Treatment is then increased as required.

Deciding when to start drug therapy for Parkinson’s disease should be individually tailored to a patient’s symptoms, circumstances and comorbidities. Treatment is indicated when symptoms impact on quality of life. When treatment is needed there is no evidence to support undue delay because of concerns about levodopa toxicity or the development of treatment resistance.³ The aim is to control symptoms and maintain an ‘on’ state.

Some drugs with good symptomatic benefit are speculated to have a role in neuroprotection and some specialists advocate their use from the time of diagnosis.⁴ Delayed start trials have been used to try and differentiate symptomatic from disease-modifying effects. A recent delayed start study of rasagiline, a monoamine oxidase B inhibitor, in treatment-naïve patients with mild Parkinson’s disease showed a small benefit in the low-dose (1 mg) treatment group. This was not seen with the 2 mg dose and a clear explanation for this has not been established.⁵ Further studies are needed before such treatments are considered truly disease modifying. Until a drug is unequivocally proven to slow disease progression, the time to commence treatment will remain contentious.

Motor features of early Parkinson’s disease typically respond well to dopamine replacement therapies. The choice of drug therapy (Table 1) includes levodopa in combination with a dopa-decarboxylase inhibitor, a dopamine agonist or a monoamine oxidase B inhibitor. Rasagiline would be an appropriate first-line drug to consider for those with mild symptoms.

Levodopa/dopa-decarboxylase inhibitors have the highest efficacy for motor symptoms and tend to have slightly better tolerability, particularly when started in low doses. The simplest dosing regimen is to commence a set dose at a set time and thereafter monitor the efficacy in terms of the dose required for symptom relief and the duration of that response. Box 1 shows a typical levodopa dosing regimen. A three-times daily starting frequency is required due to the short half-life of levodopa.

As the disease progresses it is important to establish the dose that relieves the increasing symptoms. This usually requires increasing the frequency of dosing from three to four (and often five) times a day (Box 2) with the addition of a long-acting preparation at bedtime.

Dopamine agonists are also effective first-line drugs and may be associated with less dyskinesia than levodopa/dopa-decarboxylase inhibitors. They are available in once-daily preparations. Long-term data suggest no significant difference in outcomes between patients started on levodopa/dopa-decarboxylase inhibitors and those given dopamine agonists.⁶ It is common as time progresses to use a combination of these drugs.⁴

All patients should be appropriately counselled before treatment and monitored for adverse effects throughout their lifelong treatment course. Most adverse effects are reversible. Cardiac valvular fibrosis and pulmonary fibrosis from the ergot-derived dopamine agonists such as cabergoline and pergolide may be irrreversible and some cases require surgical intervention. This risk seems most apparent amongst patients who have had more than six months duration of treatment and in those on higher doses of ergot-dopamine agonists, although individual susceptibility factors are not yet known.⁷ Patients taking these drugs require constant monitoring and where possible switching to a non-ergot derived dopamine agonist such as pramipexole, ropinirole or rotigotine is desirable.

Non-motor adverse effects of dopaminergic therapy include nausea, postural hypotension, cognitive symptoms, hallucinations, psychosis, hypersomnolence, sudden sleep episodes and impulse control disorders (gambling, compulsive behaviours and hypersexuality). Such adverse effects can occur with all dopaminergic therapies, although are more common with dopamine agonists, which can also cause peripheral oedema. The risk of impulse control disorders is significantly higher with dopamine agonists. Pretreatment counselling and sustained clinical vigilance for these disorders is essential. A reduced dose of pramipexole is needed in patients with impaired renal function and doses should be increased cautiously in older people.

Dopaminergic drugs sometimes increase the non-motor symptoms of Parkinson’s disease. Many of the drugs cause gastrointestinal adverse effects. If drug treatment is required for nausea or vomiting, metoclopramide and prochlorperazine should be avoided due to their dopamine blocking effects. Domperidone is the preferred treatment for these symptoms.

If the patient’s symptoms are not controlled it is important to exclude other diseases. As Parkinson’s disease progresses slowly, any sudden deterioration is an indicator of a co-existent medical condition, such as a urinary tract infection, or problems with compliance. Adherence can be a particular problem given the frequent dosing schedule of levodopa preparations, but may be helped by providing the medicines in a multidose pack.

Sustained failure to achieve adequate symptom control with a particular levodopa or dopamine agonist regimen should prompt an increase in the dose of that drug or consideration of combination therapy.

A fluctuating or erratic treatment response in early Parkinson’s disease may reflect variable absorption of oral therapy. Separating levodopa therapy from meals can improve absorption. Consideration of drugs which provide more continuous dopaminergic stimulation such as once-daily pramipexole or the rotigotine patch may be helpful.

Nocturnal symptoms are often improved with the addition of long-acting dopamine agonists (particularly if the patient has restless legs) or controlled release levodopa/dopa-decarboxylase inhibitors. Non-motor symptoms such as nocturia may also need to be addressed (Table 2).

Some patients with tremor refractory to levodopa therapy may respond to dopamine agonists. Anticholinergic drugs can cautiously be tried in younger patients and are occasionally useful in reducing saliva production. However, they can have significant cognitive adverse effects such as hallucinations, particularly in older people.

Motor and non-motor fluctuations occur as Parkinson’s disease progresses. This can make drug therapy challenging.¹⁰ Fluctuations include the return of symptoms at the end of the dose interval (‘wearing off’), failed symptom relief and sudden and unpredictable ‘offs’ of both motor and non-motor type. Increased dosing is also associated with so-called drug-induced dyskinesias resembling choreiform movements which occasionally can be localised, but generalise as the disorder progresses. These can occur in peak dose and diphasic* patterns.

‘Wearing off’ between doses can be managed by increasing the dose, reducing the dose interval (if using levodopa/dopa-decarboxylase inhibitors) or adding other drugs. Entacapone is a further inhibitor of levodopa breakdown and in combination with levodopa/dopa-decarboxylase inhibitors reduces ‘wearing off’ and increases the potency of an individual dose of levodopa. Often a dose reduction of approximately 25% is needed when entacapone is added. Dopamine agonists are also useful in smoothing out the end-of-dose ‘wearing off’ effect by reducing the severity of the ‘off’ period. Monoamine oxidase B inhibitors can also be considered in this situation. Dose failures may respond to oral rescue therapy with short-acting levodopa/dopa-decarboxylase inhibitors.

Involuntary motor movements or dyskinesias are often not troubling to patients, so they do not always require a change of treatment if good ‘on’ time is maintained. Disabling dyskinesias may require dose reduction at the risk of loss of efficacy. Amantadine has a mild to modest benefit in controlling motor symptoms and can reduce dyskinesia, however it has potential adverse effects including confusion, peripheral oedema and livedo reticularis.

Specialist referral and co-management of patients as time progresses is needed to manage the more challenging aspects of motor fluctuations. Non-oral therapies including apomorphine, intestinal levodopa infusion and deep brain stimulation can be considered when standard drug therapy fails to effectively manage motor fluctuations. All these treatments require ongoing involvement of a multidisciplinary team experienced in managing advanced Parkinson’s disease.

Apomorphine

Apomorphine is an injectable dopamine agonist which can be given as intermittent bolus doses or by continuous subcutaneous infusion. Intermittent boluses are effective rescue therapy for disabling motor ‘off’ symptoms, while continuous infusion can reduce daily ‘off’ time and reduce the required doses of oral drugs.¹¹ Apomorphine has the same potential adverse effects as oral dopamine agonists and may cause injection site reactions and skin nodules. Patients may need domperidone to prevent vomiting.

Intestinal levodopa infusion

Continuous administration of levodopa/dopa-decarboxylase inhibitors in gel form via a percutaneous enteral tube is available for advanced Parkinson’s disease with severe motor fluctuations refractory to oral therapy. Typically, patients carry an infusion pump around the waist or across the shoulder allowing continuous infusion during waking hours, with the option to extend to a 24-hour infusion to cover nocturnal symptoms if required. It overcomes complications relating to variable absorption of levodopa secondary to delayed gastric emptying and protein consumption. Usually, oral therapy can be withdrawn. Several studies, including some small randomised controlled trials have shown improvement in motor function, motor fluctuations and quality of life. Complications include all those seen in standard oral levodopa therapy. Additional complications related to the technical aspects of the infusion system, including tube removal/dislocation, local infection, peritonitis and intestinal obstruction, are reported in 20–70% of patients.¹²

Functional neurosurgery

There are two main neurosurgical options for Parkinson’s disease. The first is lesional surgery, which permanently ablates a target region to achieve either tremor control or lessen dyskinesia. The second is deep brain stimulation surgery. This is reversible and provides continuous electrical stimulation to a target from an implanted pulse generator (battery) which is adjustable via an externally applied programmer. Several randomised controlled trials have shown deep brain stimulation improves motor symptom control, reduces motor fluctuations and improves quality of life in people with advanced Parkinson’s disease.^13-15 Sustained motor benefit over 10 years has been demonstrated.¹⁶ Often dopaminergic drug therapy can be significantly reduced following deep brain stimulation which is of particular benefit when the drugs are difficult to tolerate.

Both forms of functional neurosurgery carry immediate perioperative risk and deep brain stimulation carries additional risks associated with the implanted hardware and stimulation field effect. Deep brain stimulation is not a cure, and inevitably symptoms of Parkinson’s disease progress, but possibly at a slower rate.¹⁷ Australian referral guidelines for deep brain stimulation are available.¹⁸

Patients with Parkinson’s disease may have autonomic dysfunction, neuropsychiatric symptoms and cognitive impairment. Non-motor symptoms contribute significantly to the morbidity of Parkinson’s disease. Interestingly, some of these are present as part of the ‘off’ phenomena and remain responsive to levodopa, but many are not and warrant management in their own right. Adverse effects of dopaminergic therapies often overlap with non-motor symptoms so the combined opinion of movement disorder specialists, neuropsychiatrists and other specialists is often important. Common non-motor problems and possible treatment options are outlined in Table 2.

Parkinson’s disease is a progressive neurological disorder with motor and non-motor features. It has significant cost and burden of care to the community over a prolonged course. Treatment is aimed at maintaining continuous relief of motor and non-motor symptoms. Drugs may be necessary, but are not sufficient to maintain quality of life in the long term. As the disease progresses, specialist referral and allied health involvement is important. The patient will need collaborative assistance from general practitioners, movement disorder specialists, neuropsychiatrists and allied health professionals.

Conflict of interest: none declared

*Diphasic dyskinesia occurs as the levodopa concentration rises and then falls