Parkinson's Disease Clinic & Research Center

How is Parkinson's Disease Treated?

At this time no treatment has been shown to slow or stop the progression of Parkinson's disease. Instead, health care providers target therapy to treat the most bothersome symptoms. For this reason, there is no standard or "best" treatment for Parkinson's disease. A number of treatment approaches help patients with Parkinson's disease. These approaches include: general lifestyle modifications (rest and exercise), dietary considerations, physical therapy, speech therapy, medication therapy and surgical therapy.

Medications for Parkinson's disease

A number of medications are available for the treatment of motor symptoms of Parkinson's disease. Because individuals with Parkinson's disease experience a range of motor symptoms and symptom severity, the choice of medication (and whether to treat with medication) varies considerably between individuals. Moreover, over time, the dose of medication(s) may need to be increased or new medications added.

Levodopa (carbidopa/levodopa; Sinemet®, Atamet®, and Parcopa®)

The introduction of levodopa (or L-dopa) 40 years ago revolutionized treatment of Parkinson's disease. Although Parkinson's disease is characterized by a loss of neurons that contain and release dopamine, oral or intravenous dopamine is not effective because like other charged amino acids, it does not pass the blood/brain barrier. However, levodopa (a precursor of dopamine) is transported to the brain and is then transformed into dopamine. For most individuals, treatment with levodopa reduces the symptoms of slowness, stiffness, and tremor. To prevent blood amino acid decarboxylases from breaking down most of an administered does of levodopa before it reaches the brain, levodopa is always combined with an inhibitor of this enzyme. In the US, the dopa decarboxylase inhibitor is carbidopa, whereas in Europe benserazide is used. Many patients need a minimum of 75 mg/d of carbidopa to avoid the nausea that occurs if levodopa is converted to dopamine systemically.

Although levodopa remains the single most effective treatment for Parkinson's disease, treatment over a number of years may lead to variability in an individual's response to treatment, called "motor fluctuations." The fluctuating response to levodopa can be broadly divided into "on" and "off" periods. During an "on" period, a person can move with relative ease often with reduced tremor and stiffness. "Off" periods describe those times when a person has greater difficulty with movement. A common time for a person with Parkinson's disease to experience an "off period" is just prior to taking the next dose of levodopa, and this experience is called "wearing off." Another form of motor fluctuation is uncontrolled writhing movement of the body or a limb, which is called "dyskinesia." About 40% of patients treated with levodopa will develop motor fluctuations within six years of treatment.

Levodopa is rapidly absorbed from the small intestine. Most patients experience improvement in symptoms about 30 minutes after a dose, and the benefit lasts about 3-5 hours. However, the duration of benefit may range from as long as a day to as short as an hour. Food (in particular, protein-rich food) delays absorption of levodopa by the gastrointestinal tract and delivery into the bloodstream. Thus, patients are often instructed to take levodopa 1 hour before meals to maximize the benefit of an individual dose.

Levodopa is also available in a "controlled-release" (CR or SR) formulation. Controlled release levodopa provides a longer duration of action by increasing the time it takes for the gastrointestinal tract to absorb levodopa. However, because the controlled release formulation only allows 70% of the levodopa to be absorbed by the gastrointestinal tract, it may be necessary to increase the amount of levodopa taken when a person is switched from standard (or immediate release) levodopa to controlled release levodopa, in order to obtain the same benefit.

Levodopa preparations
Standard release preparations
carbidopa/levodopa (Sinemet® or Atamet®)
available in 10/100, 25/100, or 25/250 tablets

Parcopa® is an accelerated release preparation and is available in 10/100, 25/100, or 25/250 tablets

Extended release preparations
levodopa/carbiopa (Sinemet CR®) 25/100 or 50/200 tablets

Side effects include nausea, vomiting, dry mouth, dyskinesias, and dizziness. In some individuals, levodopa may cause confusion, hallucinations, or psychosis. Motor fluctuations develop in about 40% of individuals treated for 4-6 years.

Catechol-O-methyl transferase (COMT) inhibitors

Recently, a new class of enzyme inhibitors, called COMT inhibitors, has been developed. Like carbidopa, COMT inhibitors prevent the breakdown of levodopa. Their main effect is to prolong the duration of action of a dose of levodopa. Since COMT inhibitors do not contain levodopa, they must be taken with levodopa in order to have any benefit. COMT inhibitors may be prescribed when an individual experiences "wearing off," particularly when dopamine agonists (see below) are not tolerated. If dyskinesias develop after starting a COMT inhibitor, the dose of levodopa may need to be reduced. A recent study has shows that entacapone when used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures (Olanow et al, 2004).

COMT inhibitors

Entacapone (Comtan®)--available in the United States and many other countries.
200 mg tablets usually given with each dose of levodopa.

Tolcapone (Tasmar®)--available in the United States, but not Canada or Europe.
100 mg and 200 mg tablets; generally given three times a day. Because liver toxicity has occurred in patients taking tolcapone, it is only indicated for patients whose symptoms are not adequately controlled by other medications (including entacapone). Patients taking tolcapone must have blood drawn before initiating treatment and then periodically to monitor liver function (every 2-4 weeks for the first 6 months of treatment and thereafter when clinically relevant).

Side effects for both of these medications include diarrhea, vivid dreams, visual hallucinations, drowsiness, urine discoloration, and dyskinesias. Fulminant hepatic failure has been reported in are patients receiving tolcapone.


Combined carbidopa, levodopa and entacapone

This preparation combines all 3 medications in one pill, which may be more convenient but may not be as flexible as taking the medications individually.

Doses:

Stalevo® 50: 50 mg levodopa, 12.5 mg carbidopa, and 200 mg entacapone

Stalevo® 100: 100 mg levodopa, 25 mg caridopa and 200 mg entacapone

Stalevo® 150: 150 mg levodopa, 37.5 mg carbidopa, and 200 mg entacapone

Stalevo® 200: 200 mg levodopa, 50 mg carbidopa, and 200 mg entacapone

Side effects of this combined preparation are the same as for levodopa and entacapone and include: diarrhea, vivid dreams, visual hallucinations, drowsiness, urine discoloration and dyskinesias.

Dopamine agonists

Dopamine agonists differ from levodopa, since they do not have to be modified by brain enzymes in order to activate dopamine receptors. They may be used in place of levodopa or in combination with it. Although treatment with dopamine agonists appear to cause motor fluctuations less frequently than levodopa, dopamine agonists are more likely to cause a number of side effects (such as nausea, somnolence, postural hypotension, hallucinations and lower extremity edema), particularly in patients over 70 and those with baseline cognitive deficits. Thus, in prescribing dopamine agonists, the treating physician must weigh the potential benefits and adverse effects.

There are two commonly prescribed oral dopamine agonists in the United States: pramipexole and ropinirole. Apomorphine, a subcutaneously administred dopamine agonist, was approved for use in the United States in 2004. The various dopamine agonists differ in several respects, including chemical structure, duration of action, and side effects. Bromocriptine and the recently withdrawn pergolide are ergot derivatives and may rarely cause retroperitoneal, pulmonary and pericardial fibrosis.  Pramipexole and ropinirole have half-lives 6-12 hours and are therefore taken 2-4 times daily.

Pramipexole and ropinirole are not ergot compounds. Large clinical trials comparing use of these medications to treatment with levodopa showed that they can be used in early Parkinson's disease and reduce the severity of symptoms. Over the years, some differences in the effects of the dopamine agonists have emerged. One side effect is daytime sleepiness and "sleep attacks." Although this may occur with all of the dopamine agonists (and levodopa), it was first appreciated in people treated with pramipexole.

Apomorphine is indicated in patients who experience "off states" which are refractory to modifications of oral medications such as increasing the dose or frequency of dopaminergic medications or introduction a COMT inhibitor. It has a rapid onset of action, usually within 10-20 minutes but the duration of action is short, lasting only about an hour. Apomorphine is only available from specialty pharmacies. Because nausea occurs in the vast majority of patients, pretreatment with trimethobenzamide (Tygan®) is required. Initial titration and observation for side effects (syncope, hypotension) must occur in the physician's office.

The response to a particular dopamine agonist is idiosyncratic. If one dopamine agonists does not offer benefit or causes bothersome side effects, another agonist may be tried. Most dopamine agonists are given 2-4 times a day. Treatment with dopamine agonists often begins at a very low dose. The dose is increased at intervals (depending on the agent) until benefit occurs.

Two recent clinical studies observed patients with early Parkinson's disease randomly assigned to treatment with either a dopamine agonist (either pramipexole or ropinirole) or levodopa. Over the course of both trials, about half of the participants assigned to dopamine agonist treatment received supplemental levodopa because of worsening symptoms. In the final analysis of these studies, dyskinesias developed at a higher rate in the levodopa groups than the dopamine agonist groups. These findings are balanced by two other findings: those patients treated with levodopa alone had slightly better control of movement and other side effects were more common in the dopamine agonist group than the levodopa groups.

Rascol et al. (2000) followed 268 patients randomized either to ropinirole or levodopa for 5 years. In that study, dyskinesias developed in about 20% of people initially treated with ropinirole compared to about 45% of participants treated with levodopa alone. Drowsiness, hallucinations and swelling of the legs were more common in the ropinirole group than the levodopa group.

The Parkinson's Study Group studied 301 patients randomized to either pramipexole or levodopa for 2 years. Dyskinesias developed in about 10% of participants assigned to the pramipexole group compared to 31% of the levodopa group. Wearing off occurred in 24% of the pramipexole group compared 38% of the levodopa group. Drowsiness, hallucinations, generalized swelling and leg swelling occurred more frequently in the pramipexole group than the levodopa group.

The case for starting treatment with a dopamine agonist has been strengthened by the observation that dopamine agonists may slow the progression of Parkinson's disease. A recent study in which people with early Parkinson's disease were treated with levodopa or pramipexole used specialized brain imaging (called SPECT) to measure the amount of a brain protein called dopamine axonal transporter (DAT) using a radioactive marker, beta-CIT. DAT is present at the release sites of dopamine-releasing neurons from the substantia nigra. Over a 46-month period, those patients treated with pramipexole lost less DAT than those treated with levodopa. The authors of the study point out that this finding may indicate a protective effect of pramipexole on dopamine-releasing neurons. A problem in interpreting this study is that even short-term (5-6 weeks) treatment with pramipexole can change beta-CIT binding, suggesting that the difference in the amount of DAT measured may reflect an effect on the brain's production and distribution of DAT and not an effect on the health of dopamine-releasing neurons.

Preliminary results from a similar study in which people with early Parkinson's disease were treated with ropinirole or levodopa were recently presented. In this study, enrolled patients were studied using fluorodopa PET scanning to assess for dopamine neurons. Like the pramipexole study, those treated with ropinirole lost less fluorodopa signal than those treated with levodopa over the course of the study.

Dopamine agonists:

Bromocriptine (Parlodel®): 2.5 mg tablet and 5 mg capsule

Common therapeutic dose: 5-10 mg tid

Pramipexole (Mirapex®): 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg tablets

Common therapeutic dose: 0.5-1.5mg tid

Ropinirole (Requip®): 0.25 mg, 0.5, 1.0 mg 4 mg, 5 mg tablets

Common therapeutic dose: 3-8 mg tid

An extended release formulation of ropinirole has recently become available that allows one single daily dose.  The dose of ropinirole XL should be chosen to match the total daily dose of ropinirole. 

Ropinirole XL (Requip XL®): 2mg, 4mg, 6mg, 8mg, 12, 16mg, 20mg, 24mg

Common therapeutic dose: 4-20mg daily.

Apomorphine (Apokyn®): 2 ml vials or 3 ml cartridges. The cartridges are used with a reusable, multiple dose injector. Typical doses vary from 1-8 mg (.1-.8ml). The starter kit includes trimethobenzamide (Tygan®) which patients should start 3 days prior to dose titration.

Cabergoline* (Dostinex®)

Lisuride** (Dopergine®)

* Not approved in the United States for the treatment of PD

**Not currently available in the United States

Side effects include drowsiness, nausea, vomiting, dry mouth, dizziness, leg swelling, and orthostatic hypotension. Although these symptoms are common when starting a dopamine agonist, they typically resolve over several days. In some individuals, dopamine agonists may cause confusion, hallucinations, or psychosis. Sleepiness, drowsiness, or sedation may be a significant side effect of some dopamine agonists in some people, and may interfere with driving or other activities. 

Behavioral side effects occur in 5-10 per cent of patients taking dopamine agonists.  The behaviors often reflect a disorder of “impulse control” in which the patient fails to resist the behavior even when it may be distressing or may impair function socially or occupationally These behavioral changes are often compulsive and include gambling, shopping, binge eating, as well as increased sexual behaviors. These behavioral changes typically resolve once the dose of the dopamine agonist is reduced or discontinued.

The nausea associated with apomorphine may be profound. In the United States, pretreatment with trimethobenzamine (Tygan®) 250 mg 3 times daily for 3 days prior to initial apomorphine dosing is required. Some patients are able to discontinue trimethobenzamine after several weeks of treatment with apomorphine.

Other medications

A number of other antiparkinsonian medications can be used alone or in combination with levodopa or a dopamine agonist in patients with Parkinson's disease. These medications do not stimulate dopamine receptors but alter basal ganglia neurotransmission by affecting other receptors. The most commonly used medications are amantadine, anticholinergic medications, and selegiline.

Amantadine may be used alone or in combination with levodopa or dopamine agonists. Itreduces symptoms of fatigue and tremor in certain patients with early Parkinson's disease, but benefit may be short-lived. More recently, amantadine has been found helpful for people with advanced Parkinson's disease who experience dyskinesias.

Formulation: Amantadine (Symmetrel®) as 100 mg capsules or in liquid form that may be convenient for treating an individual who does not tolerate a full 100 mg dose or a person with swallowing problems.

Side effects may include difficulty concentrating, confusion, insomnia, nightmares, agitation, headache, hallucinations, edema and livedo reticularis.

Anticholinergic medications may reduce tremor and/or rigidity but appear to have little effect on bradykinesia and imbalance. They can be taken alone or in combination with levodopa. These drugs are rarely used in elderly patients or those with cognitive problems, because increased confusion can be one of their side effects. Specific anticholinergic medications include:

Biperiden HCL (Akineton®): 2 mg tablets

Benztropine mesylate (Cogentin®): 0.5 mg, 1 mg, 2 mg tablets

Trihexyphenidyl (Artane®): 2 mg and 5 mg tablets as well as liquid form

Side effects may include dry mouth, blurred vision, sedation, delirium, hallucination, constipation, and difficulty urinating.

Selegiline is an inhibitor of the enzyme MAO-B (monoamine oxidase B). Since MAO-B breaks down dopamine, inhibiting it prolongs the action of dopamine in the brain, and improves the symptoms of Parkinson's disease. It also has a mild antidepressant effect. Early studies of selegiline suggested that it may delay the progression of Parkinson's disease but this appears to have been confounded by a mild symptomatic effect. Currently there is no firm evidence that selegiline slows disease progression. Selegiline preparations include:

Eldepryl®: 5 mg capsule

Atapryl®: 5 mg tablets

Carbex®: 5 mg tablets

Zelapar is an orally disintegrating form of selegiline which comes in 1.25 mg tablets; it is usually taken once daily.

Side effects may include heartburn, nausea, dry mouth, insomnia and dizziness. Confusion, nightmares, hallucinations, and headache occur less frequently.

Rasagiline is a new MAO-B inhibitor which has been approved for monotherapy and adjunct therapy in Parkinson’s disease. It is taken once daily and is less likely to cause insomnia than the original formulation of selegiline. There are tyramine dietary precautions with this medication to prevent adverse effects on blood pressure. Patients are advised to avoid tyramine-containing food such as smoked or pickled fish, preserved meats, sausage, sauerkraut, tap beer, or ale.

Rasagiline (Azilect®) is available as 0.5 and 1 mg tablets.

Side effects include abnormal movements, headache, and fatigue.

What medications are appropriate for my patient?

The best way to identify the right medications for an individual with Parkinson's disease is to identify his or her most disabling symptom.

For an individual with the first symptoms of Parkinson's disease (for example, a mild tremor in an arm or stiffness in a leg), no medication may be necessary. Mild intermittent symptoms (particularly when it involves the non-dominant arm) may not limit activity. At this early stage, adequate rest, a balanced diet, and an exercise program that emphasizes range of motion may be the most appropriate treatments.

Over time, people with Parkinson's disease note worsening of symptoms. Common symptoms that may limit activity include: tremor, slowness, and stiffness. The threshold for beginning treatment varies considerably between individuals. When starting medical treatment for Parkinson's disease, it is important for people to have a realistic expectation about the degree of improvement to expect from medical treatment. For most, an improvement of 20-40% is typical.

If tremor of a limb becomes a troubling symptom, treatment with an anticholinergic or amantadine may be tried. If the main symptom is slowness or stiffness of an arm and/or leg, a monoamine oxidase inhibitor, a dopamine agonist, or carbidopa/levedopa may be used. As discussed in the section describing dopamine agonists, treatment is often initiated with a dopamine agonist, so long as the dopamine agonist is effective and does not cause troubling side effects. For exercise-induced dystonia, an anticholinergic may be helpful. Symptoms of fatigue are occasionally helped by treatment with amantadine or an monoamine oxidase inhibitor. Because side effects of dopamine agonists are more common in older individuals, the age of a person with Parkinson's disease may influence which medication your doctor recommends. For example, many experts recommend levodopa as a first line of therapy for individuals older than 70. For individuals younger than 70, dopamine agonists are often recommended as first line therapy while levodopa is reserved for those individuals who either do not respond adequately to a number of dopamine agonists or experience intolerable side effects.
The progression of Parkinson's disease varies considerably between individuals. Over time, many people find that they do not obtain the same degree or duration of relief from a dopamine agonist or levodopa as they had previously. Increasing the dose or frequency of may resolve this problem. If raising the dose of a dopamine agonist results in side effects (drowsiness, confusion or nausea), a trial with one of the other dopamine agonists may be indicated. Alternatively, adding levodopa to treatment with a dopamine agonist may be appropriate.

For patients who have not started dopaminergic therapy, the development of postural instability may signal an appropriate time to begin or adjust therapy, since falls can cause significant morbidity.

One of the most frustrating symptoms of advanced Parkinson's disease is longer periods of time spent when movement is poor, the "off state." A number of interventions that may reduce the period of time spent in the off state includes: 1) increasing the dose or frequency of a dopamine agonist; 2) increasing the dose or frequency of levodopa; 3) beginning treatment with a COMT inhibitor; or beginning treatment with a monoamine oxidase inhibitor. Because protein-rich foods interfere with the absorption of levodopa, many who experience response fluctuations choose to eat the majority of their daily protein during the evening meal, when they are less active. If the individual continues to experience disabling "off states," treatment with apomophine may be considered. If these adjustments are unhelpful (and the patient still experiences benefit from levodopa treatment), surgical treatments of Parkinson's disease may be considered.

Dyskinesia is typically a symptom of too much levodopa or dopamine agonist. This problem may be helped by reducing the dose of levodopa or a dopamine agonist or by increasing the interval between doses. If this strategy results in prolonged "off periods," then an alternative would be to start amantadine. For some people who do not respond to these adjustments, surgical treatments of Parkinson's disease may be considered.

References:

Hauser RA, Zesiewicz TA.  Advances in the pharmacological management of early Parkinson’s disease. 2007; 13: 126-132.

Olanow CW, Kieburtz K, Stern M, et al Double-blind, Placebo-Controlled Study of Entacapone in Levodopa-Treated Patients With Stable Parkinson Disease. Arch Neurol. 2004;61:1563-1568.

Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. JAMA 2000 284:1931-8.

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