Treatment of Parkinson’s disease

Introduction

The introduction to the Canadian market of three new drugs for the management of Parkinson’s disease (PD) in the last 2 years (one of which has been withdrawn due to rare hepatic toxicity) has left practitioners with a confusing array of choices. Here are two basic principles:

• The treatment of PD is not entirely based on medication or surgery. Education, counseling, physiotherapy, occupational therapy, speech and language therapy, nutritional advice, and other treatment approaches may all be of considerable importance.

• Making a diagnosis of PD does not necessarily mean that medical therapy needs to be started immediately. There is no proven therapy to slow down disease progression and certainly no cure. Thus, treatment should be initiated when justified by symptoms. When to start will depend upon the particular needs of the individual.

Classes of medication

There are three broad classes of medication for the symptomatic management of Parkinson’s disease. Anticholinergic medications were traditionally thought to restore the balance between dopamine and acetylcholine in the basal ganglia that is disrupted in PD.[1] However, these medications are also known to inhibit dopamine reuptake.[2] Although they may be effective for tremor, they are less beneficial for the poverty of movement, which is the major source of disability in PD, and their use may be complicated by cognitive side effects.

Most medications act to stimulate the release of dopamine from surviving nerve terminals (amantadine) or to replace dopamine. This can be accomplished in the form of a precursor (levodopa) or a synthetic dopamine receptor agonist. Finally, some medications act to inhibit the breakdown of levodopa (catechol-O-methyltransferase [COMT] inhibitors) or dopamine (COMT or monoamine oxidase [MAO] inhibitors). These will all be discussed with respect to their appropriate indications and are summarized in the Table.

The newly diagnosed patient

Therapy should be initiated when indicated by symptoms. Although the gold standard of treatment for PD is still levodopa combined with a peripheral decarboxylase inhibitor (carbidopa or benserazide), the long-term use of levodopa-containing preparations is associated with numerous complications, including fluctuations in motor function and the emergence of involuntary movements, collectively referred to as dyskinesias. These movements are distinct from the rhythmic rest tremor characteristic of PD, do not occur in people with an intact dopamine system despite significant doses of levodopa, and are much more likely to occur in younger patients. Recent evidence indicates that the emergence of dyskinesias can be significantly delayed and the primary symptoms of PD can be adequately treated by the use of a dopamine agonist alone (see below). Thus, in younger patients, the introduction of levodopa should be delayed and therapy should be initiated with an agonist or with amantadine. Levodopa should be added when dictated by symptoms. In older patients, the agonists may be less well tolerated and dyskinesias are less of an issue, so initiation of therapy with levodopa is still the preferred approach.

Amantadine

The benefits of amantadine were discovered fortuitously, when it was recognized that parkinsonian nursing home residents being treated for prevention of influenza experienced an improvement in their parkinsonism.[3] It has traditionally been thought that the primary mechanism of amantadine’s action is the enhancement of dopamine release from surviving dopamine neurons. This may be the case, although dopamine release probably reflects amantadine’s properties as a weak antagonist of excitatory amino acid (NMDA) receptors. Amantadine also has side effects reminiscent of anticholinergic medications and is prone to cause confusion in the elderly. As it is excreted almost unmetabolised by the kidneys, the dose must be appropriately adjusted in patients with reduced creatinine clearance. Amantadine provides modest reduction of parkinsonian symptoms when given as monotherapy, and its NMDA antagonist properties provide at least a theoretical framework for reducing the rate of disease progression (and its use is an independent predictor of prolonged survival in patients with PD).[4] Therefore it is an entirely legitimate choice for initiating treatment in the younger patient with PD, but probably best avoided in the elderly. Recent evidence indicates that it may be extremely useful as an adjunct to other therapies for the suppression of levodopa-induced dyskinesias.[5,6] In addition to dopaminergic side effects and confusion, it may cause peripheral edema and livedo reticularis.

The dopamine agonists

These compounds stimulate dopamine receptors directly. Unlike levodopa, they do not depend upon enzymatic conversion to an active agent, nor do they depend upon a saturable transport system for passage across the blood-brain barrier. The older agents are bromocriptine (Parlodel) (usual dose 15 mg to 40 mg/day) and pergolide (Permax) (usual dose 1.5 mg to 4.5 mg/day). These compounds are both ergot derivatives. In addition to the side effects that arise from dopaminergic stimulation (nausea, vomiting, postural hypotension, confusion, and hallucinations), use of these agents may rarely result in problems related to their ergot properties—a painful, red, vasculitic swelling of the legs (erythromelalgia) and pleural and pulmonary fibrosis. The two newer agonists pramipexole (Mirapex) and ropinirole (ReQuip) are not based on an ergot structure; while they cause the same dopaminergic side effects as bromocriptine and pergolide, they should be devoid of these latter two complications. Cabergoline (Dostinex) is another ergot compound with a long duration of action, but it is not available in North America.

Are the new agonists better than the old ones?

There has been relatively strong evidence supporting the use of the new agonists as monotherapy in patients with early PD. Both pramipexole (usual dose 1.5 mg to 4.5 mg/day) and ropinirole (usual dose 9 mg to 24 mg/day) are generally well tolerated and effective, and their use is associated with fewer dyskinesias than levodopa[7,8] and, at least in the case of pramipexole, a lower incidence of predictable fluctuations.[8] Furthermore, they are not subject to the possible development of erythromelalgia and pleural fibrosis. In contrast, it has traditionally been thought that the older, ergot-derived dopamine agonists may be less effective as monotherapy, although widely assumed that, like the new agents, they are less likely to induce dyskinesias than levodopa.[9,10] Two recent studies suggest that the older agonists may be more effective than previously thought. In a double-blind comparison of ropinirole versus bromocriptine monotherapy, while ropinirole somewhat outperformed bromocriptine in most measures, the differences were not significant and many patients were able to tolerate monotherapy without levodopa "rescue" for up to 3 years.[11] A very recently reported European multicentre study of pergolide monotherapy (not yet published) indicates that it, too, is effective as monotherapy for up to 3 years and similarly associated with fewer dyskinesias. Thus, while it is clearly preferable to have a variety of agents to choose from, as any given patient may do better with one drug than another, apart from the issue of ergot-related toxicity, it is not clear that the newer agents offer any consistent advantage over the older agonists.

Excessive daytime sleep

It is well recognized that PD may itself be associated with alterations in the sleep-wake cycle. Parkinson’s patients may have interrupted sleep for a variety of reasons and may sleep excessively during daytime. In addition, virtually all the medications used for the treatment of PD may result in dose-related sedation. However, a recent report suggested that the new agonists might result in attacks of sudden sleep without warning.[12] This includes abrupt loss of awareness during activities such as driving. A recent survey of our clinic population suggests that this phenomenon is indeed more common than had previously been recognized, but following correction for age, disease duration, and medication dose, it is likely to affect patients treated with any antiparkinson medication equally.[13] Fortunately, the emergence of abrupt sleep attacks is likely to be predicted by the presence of excessive daytime sleepiness as measured on the Epworth scale. For the time being, however, government-mandated warnings on driving apply to the new agonists only.

The patient with established disease

In patients already on treatment who are doing well, there is no indication to change medications. If a patient on an immediate-release levodopa preparation develops either predictable dose-related fluctuations in motor function (end-of-dose deterioration or "wearing off") or peak-dose dyskinesias, he or she should be switched to a controlled release preparation of levodopa. The only such preparation available in Canada is Sinemet CR (levodopa and carbidopa), which has a lower bioavailability than the comparable immediate release preparations. Thus, the total daily dose of Sinemet CR should be 25% to 30% higher than that of an immediate release preparation in order to achieve equivalence. Because of strong theoretical evidence that pulsatile stimulation of dopamine receptors is a major factor contributing to the emergence of long-term motor complications,[14] some neurologists prefer to initiate therapy with a controlled release preparation, even before the emergence of fluctuations. However, a randomized controlled study comparing the two preparations found no significant difference in the incidence of motor complications, but a surprisingly low rate in both groups, possibly reflecting careful use.[15]

In patients with predictable dose-related fluctuations in motor function, the duration of benefit from each dose of levodopa can be prolonged using a catechol-O-methyltransferase (COMT) inhibitor.[16-18] Tolcapone was the only such agent available on the Canadian market and was withdrawn because of rare but sometimes fatal hepatic toxicity. A newer agent, entacapone, has a similar mechanism of action and results in similar benefit, but is thought to be devoid of hepatic toxicity; it was released on the U.S. market in October 1999 but is not yet available in Canada. Although these agents can be highly effective for the treatment of fluctuations, they can also potentiate dyskinesias, and their use may require a reduction in levodopa dose.

Dopamine agonists are an excellent choice as adjunctive therapy in patients with fluctuations or dyskinesias. These agents potentiate the effects of levodopa, have a longer duration of action, and are less likely to induce dyskinesias at an equivalent level of therapeutic benefit. Either the older or the newer agents can be used.

Several practice points should be remembered when using these drugs. They should be introduced slowly and the dose should be increased to effective levels in a gradual fashion, often over several weeks. During this time, it may be necessary to gradually reduce the dose of levodopa in order to minimize dyskinesias. Nausea, vomiting, and postural hypotension can be minimized by the use of domperidone (Motilium) (10 mg q.i.d. to 20 mg t.i.d.). It is commonly misconceived that dopamine agonists have failed, either because of intolerable side effects or because of inadequate benefit. This frequently results from either inappropriately rapid dose titration or from failure to prescribe an adequate dose.

Surgery

Stereotactic surgery is generally helpful for patients who have responded to levodopa in the past, but whose response is now suboptimal, or particularly those who suffer from dose-limiting medication-induced dyskinesias. Surgery should not be regarded as a replacement for optimizing medication. Surgery is dealt with in detail in "Surgery for Parkinson's disease."

Other complications

Autonomic dysfunction resulting in postural hypotension, urinary dysfunction, constipation, and sexual dysfunction are all relatively common in PD.

Psychiatric and cognitive problems are also common. While the basis for depression (primary neurochemical alterations or secondary reaction to living with a chronic illness) is still the source of some debate, antidepressant medications are typically helpful. Although there have been numerous anecdotal reports of extrapyramidal complications associated with the use of selective serotonin reuptake inhibitors,[19,20] both controlled trials and abundant clinical experience suggest that these agents are usually well tolerated and effective in depressed patients with PD. Venlafaxine (Effexor), a serotonin and noradrenaline reuptake blocker, is also commonly used in our clinic. For refractory patients, electroconvulsive therapy may be extremely helpful and characteristically helps the motor manifestations of PD as well. Depression, anxiety, and psychosis in PD are covered in more detail in "Depression, anxiety, and psychosis in Parkinson's disease."

Psychosis is a somewhat less frequent but serious complication of therapy. Although demented patients with PD or those suffering from diffuse Lewy body disease are more prone to them, hallucinations, delusions, and inappropriate sexual aggression can occur in treated patients with normal cognition. The first step is to rule out any intercurrent illness, sleep deprivation, metabolic disturbance, and so on, that could act as a precipitant. Once this is done, antiparkinson medication should be reduced or withdrawn, beginning with those agents with the lowest therapeutic index. Thus, anticholinergics, selegiline, and amantadine should be withdrawn immediately. As it may take several days to see an improvement in the psychosis, one should wait before making further changes, if practical. Then, if necessary, the dose of dopamine agonist should be gradually reduced, followed by reductions in the dose of levodopa. Great caution is necessary in doing this, however, as there may be serious exacerbation of parkinsonian symptoms, including precipitation of a neuroleptic-malignant-like state. If the psychosis persists despite maximally tolerated reductions of antiparkinson medication, some thought should be given to cautious use of an atypical neuroleptic, such as clozapine (Clozaril)[21] or quetiapine (Seroquel).[22] Electroconvulsive therapy may be helpful in patients with a clear sensorium and intact cognition.

Other agents

As suggested above, anticholinergics no longer play a significant role in the treatment of PD because of their limited efficacy and their propensity to cause confusion and psychosis. They should be avoided entirely in those over 60, but may occasionally be helpful for the younger patient with tremor-predominant disease.

The selective monoamine oxidase-B inhibitor selegiline (Eldepryl) attracted considerable attention more than a decade ago when it was reported that its use delayed the requirement for levodopa by several months.[23] Following initial enthusiasm that this represented a neuroprotective effect, later assessment suggested that the benefit was largely symptomatic.[24] Although selegiline may be helpful in some patients with fluctuations in motor response, its use is also associated with dyskinesias and sleep disturbance, and sometimes with autonomic and psychiatric side effects. It is therefore much less widely used, particularly in view of the availability of other agents.

Drugs that interfere with excitatory amino acid transmission are already being tested to see if they may slow disease progression. In the future, a number of other compounds may be available, including neurotrophic agents, neuroimmunophilins, and inhibitors of apoptosis.

Table. Drugs used for the treatment of Parkinson's disease

A. Jon Stoessl, MD, FRCPC

Dr Stoessl is a professor of neurology at the Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre and Canada Research Chair of Central Nervous System Disorders.