Treatment Options for Parkinson's Disease

Pharmacological (Drug) Therapy for Parkinson's Disease

Since the underlying disease process of Parkinson's disease involves the death of dopamine-producing cells and the subsequent reduction of dopamine available in the brain, the objective of treatment is to increase the amount of dopamine by using agents that either:

  • Increase dopamine levels in the brain
  • Stimulate dopamine receptors in the brain
  • Slow the metabolism and breakdown of dopamine in the brain and reduce the fluctuations of dopamine in the blood

To meet these objectives, there are three categories of medication used to treat Parkinson's disease, namely:

  • Levodopa - increases levels of production of dopamine
  • Dopamine agonists - stimulate the dopamine receptors by mimicking the effects of dopamine in the brain and cause the neurons to behave as if there was enough dopamine present
  • MAO-B and COMT inhibitors - slow the metabolism of dopamine in the body and keep levels of dopamine in the blood at more constant levels

In addition to the dopamine-related drugs, two other classes of drugs may be prescribed to reduce some symptoms of Parkinson's disease, namely anticholinergic drugs and antiviral drugs. They are only mildly to moderately effective and are used only in combination with other medication.

Medical management of Parkinson's disease consists medication given either alone (monotherapy) or in combinations. There is considerable debate regarding which drugs to start first, when to combine drugs, and in what order. Regardless of which medication is chosen for treatment, the dose is initiated at the lowest level possible and then slowly increased until symptom relief is achieved and side effects are tolerable.

The American Academy of Neurology and the Movement Disorder Society both concur that levodopa is the most effective drug for treatment of Parkinson's disease and that levodopa or dopamine agonists are appropriate as initial therapy for symptoms of Parkinson's disease.

To read more about the Practice Parameters of the American Academy of Neurology, please click on the following link:

http://www.aan.com/professionals/practice/pdfs/gl0096.pdf

Dopamine agonists may also be used as second-line medication as well as MAO-B and/or COMT inhibitors or as adjuncts to enhance the effects of levodopa. Anticholergic agents or antiviral drugs may also be added on second-line therapy. There is considerable flexibility regarding which medications within each class to give first, whether to give first-line drugs as monotherapy or combination therapy, and which drugs to use as second-line therapy and when to initiate the change from first- to second-line drugs.

In general, first-line medications for the treatment of initial stages of Parkinson's disease include:

  • Levodopa
  • Dopamine agonists
  • MAO-B inhibitor (The U.S Food and Drug Administration recently approved rasagiline as a first-line therapy for Parkinson's disease)

Second-line medications include:

  • Dopamine agonists
  • MAO-B inhibitors
  • COMT inhibitors
  • Anticholinergic agents
  • Antiviral drugs

Levodopa

Until recently, levodopa was considered the "golden drug" for initial symptomatic treatment of Parkinson's disease. It became available in the 1960's and represented the first dramatic breakthrough in the treatment of Parkinson's disease. It is a highly effective drug and has been shown to extend life expectancy in Parkinson's disease patients. Before levodopa was introduced, the only agent that could relieve Parkinson's disease symptoms was anticholinergic drugs for the relief of rigidity and resting tremor. Levodopa is most effective for bradykinesia (slowness of movement) and rigidity. It is less effective for resting tremor.

Levodopa brought about a revolution in Parkinson's disease treatment by reversing the neurochemical abnormality responsible for the symptoms and making dopamine available for the brain. Dopamine itself cannot cross the blood/brain barrier (a tight "net" of blood vessels that protects the brain by preventing many agents from crossing into the brain). Levodopa was the first drug that was formulated in such a way that some dopamine was able to reach the brain.

Sinemet (levodopa combined with carbidopa) is the standard formulation of levodopa for Parkinson's disease patients today. This was a significant modification of levodopa because while carbidopa does not cross the blood brain barrier, it inhibits levodopa from being metabolized into dopamine in the digestive system (outside the central nervous system) and leaves a greater concentration of levodopa available to reach the brain with each dose. Thus, Sinemet reduces the amount of levodopa necessary to achieve desired motor control. Sinemet also minimizes some of the short term side effects of pure levodopa, including nausea and vomiting.

When a Parkinson's disease patient begins treatment with levodopa, there is a dramatic improvement of symptoms. However, as time progresses, the patient begins to find that the Parkinson's symptoms recur and the dose to achieve patient comfort may need to be raised. Combining levodopa, carbidopa and entacapone (a COMT inhibitor) in a drug called Stalevo, has been found to prolong the action of levodopa, thereby, providing relief with lower doses of levodopa.

There is a slow, sustained release formulation of Sinemet available which reduces the uncomfortable side effects but is not as effective as the regular formulation since its absorption into the blood is slower than the normal dose formulation. The controlled release Sinemet is only moderately effective and does not significantly reduce motor complications in most patients. Some doctors prescribe the slow release Sinemet to be taken as the last dose before the patient goes to bed.

Levodopa is considered to be so effective for Parkinson's disease that only approximately 10% of patients with Parkinson's disease do not respond. Indeed, some physicians are of the opinion that if a patient with Parkinsonian symptoms does not respond to levodopa, other causes for the symptoms should be investigated.

Side-Effects of Levodopa

Over time, patients taking increasingly large doses of levodopa find that not only is the effectiveness reduced but major-side effects become evident. This typically takes place in about 50% of the patients after approximately five years. Some of these events occur because levodopa has a short half-life (the time it takes for half the dose of the drug to be eliminated from the body) of approximately 1.5 hours so the effect of the drug wears off quickly and symptoms reappear.

Side-effects of levodopa can have a profound effect on the quality of life of the patient and include:

  • Dyskinesia - involuntary movements (e.g., twitching, nodding, or jerking). The movements can be mild, severe, slow, or rapid. The only way to control them is to cut back on the amount of levodopa, but a return of the Parkinson symptoms quickly recurs. At this point, other medications are utilized. This is the most problematic side effect and has a significant influence on quality of life.

  • "Wearing-off" effect - this is the end-of-dose deterioration of symptoms that occurs when levodopa wears off. It may be an indication that the patient must take the drug more frequently. Often, the patient experiences symptoms of dystonia (involuntary muscle spasms which can cause abnormal movements).

  • "On-off" effect - also called the "yo-yo" phenomenon, is due to the fluctuation of dopamine levels in the blood. The patient experiences sudden, unpredictable changes in the ability to move. They may go from carrying out a motor activity normally ("on") to suddenly freezing or becoming totally rigid with parkinsonian symptoms ("off"). This can happen several times a day. The "on-off" effect usually indicates either that the patient's response to levodopa is changing or that the disease is progressing.

  • Parkinsonian symptoms are more pronounced before the patient takes the first dose of levodopa in the morning.

  • Hallucinations

  • Restlessness

  • Orthostatic hypotension (drop in blood pressure while standing)

When levodopa is introduced to patients with Young Onset Parkinson's Disease, the response to the first dose is dramatic but they are likely to develop associated side effects, primarily dyskinesia, after a few months. Those with adult onset Parkinson's disease usually manifest the same side effects after approximately 3-5 years.

Dopamine Agonists

  • Ropinirole (Requip)
  • Pramipexole (Mirapex)
  • Bromocriptine (Parlodel)
  • Pergolide (Permax) - In March 2007, the FDA notified healthcare professionals and patients that pergolide has been withdrawn from the market because it has been linked to serious damage to heart valves.
  • Lisuride (Dopergin)
  • Cabergoline (Cabaser)

Dopamine agonists mimic the effects of dopamine in the brain and cause neurons to react as if there were enough dopamine present to carry out their function. This class of medications is used either as a monotherapy (single drug) or in combination with levodopa. If used initially as a single therapy, after a certain amount of time, levodopa is added because the relief that the dopamine agonists provide is not sufficient to reduce the symptoms and improve the quality of life as the disease progresses. If levodopa is used as the initial therapy, the dopamine agonists are added in order to prolong the duration that dopamine is active in the brain and thus reduce the "wearing off" effect and dyskinesia.

Dopamine agonists are not as effective as levodopa particularly in alleviating rigidity and bradykinesia. However some doctors feel that since dopamine agonists do have some beneficial effect on parkinsonian symptoms, and the side effects are not as severe as those of levodopa, it is worthwhile to initially prescribe a dopamine agonist and then add levodopa later as needed. Some studies indicate that dopamine agonists as monotherapy can reduce symptoms for up to three years and reduce the risk of developing side effects (dyskinesia and motor fluctuations) for up to 4-5 years. Another advantage of dopamine agonists is that they have a longer half-life than levodopa. Their use does not induce the "wearing off" effect or dyskinesia and may actually moderate these effects when combined with levodopa.

In studies comparing quality of life in Parkinson's disease patients following 4 years of taking either levodopa or dopamine agonists, the resulting quality of life scores were comparable, though there were fewer dyskinesias reported for those patients taking the dopamine agonists (pramipexole or ropinirole). More long-term data is necessary before decisions can be made to reduce reliance on levodopa.

One of the major decisions that needs to be made by the patient and the doctor is whether using dopamine agonists to delay dyskinesia and possibly delay disease progression is worth the poorer control of motor symptoms which are so effectively reduced by levodopa. In addition, dopamine agonists are associated with more side effects when used as a monotherapy than when combined with levodopa.

An additional issue that doctors should consider before prescribing dopamine agonists is the burden of cost on the patient since dopamine agonists are significantly more expensive than levodopa.

Side-Effects of Dopamine Agonists

Dopamine agonists do have some significant side effects which are mostly cognitive in nature and can significantly interfere with daily living. These include:

  • Paranoia
  • Hallucinations
  • Confusion
  • Nightmares
  • Nausea
  • Vomiting

Some patients develop dyskinesia as well but these are usually not as severe as those seen following levodopa.

Because of the nature of these complications, dopamine agonists are not given to patients who already suffer from any type of cognitive impairment. Recent data has shown a possible link between ergot-based dopamine agonists, such as bromocriptine and pergolide, and dysfunction of cardiac valves. As a result, non-ergot based dopamine agonists such as ropinirole and pramipexole should be tried before the others.

In general, the data so far suggests that dopamine agonists are a significant addition to the arsenal of drugs that are effective in reducing symptoms of Parkinson's disease as well as moderating the side effects associated with levodopa. However, because response to the drugs is so variable, each doctor must evaluate carefully with the patient the choice of drugs as well as the timetable for adding or combining new drugs.

Neupro Transdermal Delivery System

A novel transdermal delivery system (Neupro patch) has recently emerged for the treatment of patients with early Parkinson's disease with a dopamine receptor agonist drug called rotigotine . The patch is applied once a day to the skin and continuously releases the drug through the skin for a period of 24-hours.

In March 2008, the manufacturer of Neupro (Schwarz Pharma) informed healthcare professionals and patients of the recall of Neupro because of the formation of rotigotine crystals in the patches. When the rotigotine crystalizes, less drug is available to be absorbed through the skin and, therefore, the efficacy of the product may vary. Neupro will not be available in the U.S. by the end of April 2008. Healthcare professionals should not initiate any new patients on Neupro and should begin to gradually down-titrate all patients currently using the product per the guidelines in the product labeling. Patients should not abruptly discontinue therapy because abrupt withdrawal of dopamine agonists has been associated with a syndrome resembling neuroleptic malignant syndrome or akinetic crises.

Monoamine Oxidase Type-B (MAO-B) Inhibitors

There are two MAO-B inhibitors that are used in the treatment of Parkinson's disease, selegiline and rasagiline. Dopamine is one of the brain chemicals known as monoamines which are broken down by a protein known as oxidase. MAO-B drugs inhibit or limit the action of oxidase and prevent the breakdown of dopamine in the brain resulting in an enhanced and prolonged effect of levodopa. There has also been considerable debate as to whether the MAO-B drugs used for Parkinson's disease are neuroprotective and possibly delay the progression of Parkinson's disease.

There are two MAO-B inhibitors that are used in the treatment of Parkinson's disease, selegiline and rasagiline.

Selegiline

The most widely used MAO-B inhibitor is selegiline (e.g., Eldepryl, Deprenyl). Selegiline is used as an adjunct to levodopa since it increases the half-life of dopamine in the brain. There has been considerable debate as to whether selegiline is neuroprotective and possibly delays the progression of Parkinson's disease.

When given to patients in early stage of Parkinson's disease as a monotherapy, some studies suggest that selegiline delays the need for Sinemet possibly by as long as 9 months. Other studies have shown that there is no support for giving selegiline as an initial monotherapy. When given later in disease progression, selegiline boosts the effect of levodopa and improves the problem of fluctuations of motor response in about one half to two thirds of patients. The drug is easily tolerated. In general, selegiline is considered to be only moderately effective resulting in its being prescribed more as an adjunct medication rather than as a monotherapy.

Side effects of selegiline include:

  • Nausea
  • Orthostatic hypotension (low blood pressure when standing)
  • Insomnia (difficulty sleeping)
  • Confusion
  • Abdominal pain
Rasagiline

On May 17, 2006, the U.S. Food and Drug Administration (FDA) approved a newer MAO-B drug called rasagiline (Azilect) for the treatment of Parkinson's disease. This drug was approved for use as an initial single drug therapy (monotherapy) for patients with early Parkinson's disease and in combination with levodopa in patients with more advanced Parkinson's disease. Various studies have indicated that rasagiline when used in levodopa-treated patients is effective for:

  • Reducing motor fluctuations
  • Reducing mean daily "off" time
  • Improving UPDRS scores for activities of daily living

When rasagiline was studied as a monotherapy, total UPDRS scores improved by 30% or more. Studies are ongoing regarding the possibility of rasagiline slowing the rate of progression of Parkinson's disease.

Rasagiline is well tolerated and is not associated with side effects.

A study published in 2005 in the British Journal of Cancer (Volume 92, Issue 1; pp. 201-205) reported that Parkinson's disease patients may be at increased risk for developing a type of skin cancer known as malignant melanoma. During development, this type of skin cancer was also diagnosed in a small number of patients treated with rasagiline (Azilect). Since there is some evidence that patients with Parkinson's disease may be at increased risk for developing melanoma, currently there is no definitive proof that treatment with rasagiline (Azilect) is associated with an increased risk for developing melanoma. It is currently recommended that patients receiving treatment with rasagiline (Azilect) should undergo periodic check-ups from a dermatologist to monitor for signs of melanoma and other types of skin cancer.

While taking MAO-B inhibitors, caution must be taken regarding adverse drug interactions with other medications, including many nonprescription cold medications that contain pseudoephedrine, (a decongestant) and dextromethorphan (a cough suppressant).

Catechol-O-Methyltransferase (COMT) Inhibitors

  • Entacapone (Comtan)
  • Tolcapone (Tasmar)

COMT inhibitors prolong the effect of levodopa by blocking the enzyme known as catechol-O-methyltransferase (COMT) that breaks down dopamine in the liver and other organs. As a result, many of the adverse effects of levodopa which result because of sudden drops or fluctuations in the levels of levodopa are reduced. This reduces the "off" duration which is seen in motor complications of levodopa. COMT inhibitors also decrease the "wearing off" effect.

Tolcapone

Tolcapone (Tasmar) is a very potent drug which easily crosses the blood/brain barrier and is used as an adjunct to levodopa. Because it increases the half-life of levodopa, the patient can reduce levodopa intake by 25-30%.

The major side effect of tolcapone is liver toxicity leading to liver failure. Because of this, tolcapone is given only to Parkinson's disease patients who are not responding to other medications. Once a patient begins taking tolcapone, they require very close monitoring of liver function. The Food and Drug Administration suggests that patients be monitored every two weeks for the first year; then every four weeks for the following 6 months; and every eight weeks, thereafter. The FDA also suggests that if a patient does not exhibit substantial improvement within the first 3 weeks of taking the first dose, the drug should be withdrawn.

Other adverse effects of tolcapone may include:

  • Dyskinesia
  • Nausea
  • Sleep disorder
  • Muscle cramps
Entacapone

Entacapone (Comtan) is similar in composition to tolcapone but does not cross the blood/brain barrier. It is used as an adjunct to levodopa and is effective in reducing the "wearing-off" effect. Because of the lower risk of complications involved with this drug, it is the COMT inhibitor usually prescribed.

The main adverse effects associated with entacapone include:

  • Urine discoloration
  • Nausea
  • Dyskinesia

Anticholinergic Agents

  • Trihexyphenidyl (Artane)
  • Benztropine (Cogentin)

Anticholinergic agents do not act directly on dopamine as do the other drugs previously mentioned. Rather, they decrease the effect of acetylcholine which counteracts the benefits of dopamine in the brain. They are most effective for the control of tremor. Even so, they are only moderately beneficial.

Anticholinergics were the drug of choice for Parkinson's disease before the discovery of levodopa. Since only about half the people who take anticholinergics respond, and even then only for a brief time, they are not used often. Also, since tremors are often not such a disabling aspect of Parkinson's symptoms there is less need to add this medication to control them.

Side-Effects of Anticholinergic Agents

Adverse reactions to anticholinergic drugs include:

  • Dry mouth
  • Nausea
  • Urine retention
  • Constipation
  • Memory loss
  • Confusion
  • Hallucinations

Because of the side effects, anticholinergics are rarely prescribed people over 70 years of age or for any patient already experiencing mental impairment. In some circumstances, doctors find that older people who cannot tolerate anticholinergics may tolerate antihistamines (e.g., Benedryl) and antidepressants (e.g., Elavil) that have similar effects on Parkinson's symptoms. In general, anticholinergic drugs are not widely used in treatment of Parkinson's disease because of their minimal efficacy and the side effects associated with them.

Antiviral Drugs

The most commonly used antiviral drug is amantadine (Symmetrel) which reduces symptoms of Parkinson's disease by blocking the reuptake of dopamine resulting in an increase in the availability of dopamine in the brain. After several months, the effectiveness wears off in approximately one third to one half of the patients. Amantadine is most useful to treat levodopa-induced dyskinesia. Amantadine is considered as only moderately effective resulting in its being prescribed more as an add-on medication rather than as a monotherapy.

Side effects include significant cognitive impairment (e.g., hallucinations) and for this reason, antiviral drugs are usually not given to older people or to people who already experience cognitive symptoms. Other side effects include:

  • Blurred vision
  • Depression
  • Edema
  • Confusion

Other Medications for Parkinson's Disease

There are several other medications that have not been approved by the Food and Drug Administration for treatment of Parkinson's disease symptoms but may be used to help control various symptoms. For example, botulinum toxin injections may be administered to reduce saliva production and drooling. Collagen injections may help voice and speech disorders by augmenting the vocal fold.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS) is a rare complication of Parkinson's disease and is usually triggered by a reduction or discontinuation of antiparkinsonian drugs, especially, but not exclusively, levodopa. Additional triggers for NMS are infection and dehydration. Symptoms include high fever, increased rigidity and exacerbation of Parkinson's disease symptoms, disturbances of consciousness, disturbances of the autonomic system (including blood pressure), and elevated creatine kinase levels in the blood.

It is critical for Neuroleptic Malignant Syndrome to be treated immediately as it can lead to pneumonia or renal failure. Treatment usually includes infusion of intravenous fluids, cooling to bring down fever, increasing or reintroducing antiparkinsonian medication, as well as administration of other drugs such as bromocriptine and dantrolene. There is ongoing research into the efficacy of other medications in treating NMS.

Effective Use of Parkinson's Disease Drugs

According to a Practice Parameter published by the American Academy of Neurology in 2002, the conclusions regarding initial treatment for Parkinson's disease include the following:

  • First-line treatment of newly symptomatic Parkinson's disease patients should consist of either levodopa or dopamine agonists. Levodopa is more effective for symptomatic relief but carries greater risks for dyskinesia.
  • Sustained release levodopa provides no advantage over the immediate release form of the drug.
  • Selegiline, while of limited symptomatic benefit, has no neuroprotective properties.

In 2006, the Food and Drug Administration approved rasagiline as a monotherapy for treatment of early Parkinson's disease and as add-on therapy to levodopa for moderate and advanced stages.

The American Academy of Neurology published an additional Practice Parameter for the treatment of Parkinson's disease in which the following conclusions were drawn:

  • Entacapone and rasagiline should be offered to reduce "off" time
  • Amantadine may be considered to reduce dyskinesia
  • Deep brain stimulation of the subthalamic nucleus may be considered to improve motor function, and reduce "off" time, dyskinesia, and medication usage.
  • Response to levodopa before deep brain stimulation is a good indicator of better outcome following DBS.

Treatment of Parkinson's patients is highly individualized and is based on many criteria. These include:

  • Level of disability
  • Stage of the disease
  • Age of the patient
  • Presence of comorbid conditions (e.g., dementia, hypertension)

Evaluation of these parameters helps determine when to introduce drug therapy and which classes of drugs to employ. Though there are no standard guidelines that are applicable for all patients, there are certain principles that seem to be widely accepted. These include:

  • If the patient is below the age of 70, they will usually be given dopamine agonists as the initial therapy because motor complications from levodopa are a significant issue for these patients and the dopamine agonists reduce the incidence of motor complications.

  • If the patient is above 70 years of age, they will usually be started on levodopa because:

    • older patients are less likely to be affected by motor complications from levodopa
    • levodopa is less likely to cause problems for people with comorbid conditions
    • levodopa is better tolerated than most other classes of Parkinson's disease drugs in terms of both cognitive and behavioral side effects
    • levodopa is usually used as the initial treatment for any patient who has cognitive impairment

Beyond these general principles, there is a great deal of variation in how patients are medicated. It is crucial for the patient to be under the care of a doctor who has extensive knowledge and experience in the diagnosis and treatment of Parkinson's disease. The decisions to add medications, and to raise or lower doses, are made very carefully and must be monitored by a medical professional who is intimately familiar with the nuances of the progression of Parkinson's disease as well as controlling side effects.

As the disease and level of disability progress, there are several options to manage motor complications that arise. These include:

  • Smaller and more frequent doses of levodopa
  • Adding or increasing dopamine agonists to levodopa
  • Adding MAO-B or COMT inhibitors in order to increase the half-life of levodopa
  • Adding amantadine or selegiline to reduce dyskinesia

Neuroprotective Therapy for Parkinson's Disease

The goal of neuroprotective therapy is to prevent disease progression by treating the mechanisms involved in causing Parkinson's disease. There are many studies being conducted to evaluate various agents that may possibly slow the progression of Parkinson's disease. Some of these agents include:

  • Coenzyme Q10 (ubidecarenone)- an antioxidant
  • Certain dopamine agonists - so far the indications are that the only dopamine agonist that might do so is pramipexole and possibly ropinirole. However, the current evidence is inconclusive and no definitive conclusions have been reached.
  • MAO-B inhibitors (selegiline, rasagiline)

A Practice Parmater published by the American Academy of Neurology (AAN) indicated that no treatment to date has been shown to be neuroprotective. To read more about the conclusions of the AAN regarding neuroprotective agents and Parkinson's disease, please click on the following link:

http://aan.com/professionals/practice/guidelines/Neuroprotective_PD.pdf