Patient information: Parkinson disease treatment options — medications (Beyond the Basics)

PARKINSON DISEASE OVERVIEW

There are a wide variety of medical and surgical treatments available for Parkinson disease (PD). Medical treatment includes medications, education, support, exercise, physical and speech therapy, and nutrition. For some people with advanced Parkinson disease, surgical treatment with deep brain stimulation is another option. The optimal combination of treatments depends upon the person's signs and symptoms, age, stage and severity of disease, and their level of physical activity.

The information that follows can help patients and family members to better understand the potential risks and benefits of medications. Other types of treatment are discussed separately. (See "Patient information: Parkinson disease treatment options — education, support, and therapy (Beyond the Basics)".) The symptoms and diagnosis of PD are also discussed separately. (See "Patient information: Parkinson disease symptoms and diagnosis (Beyond the Basics)".)

WHEN TO START PARKINSON DISEASE TREATMENT

The decision to start medication for Parkinson disease depends upon the severity of symptoms. The most important consideration is how much the symptoms interfere with the person's ability to perform daily activities. Another important factor is the person's personal philosophy about the use of medications. The healthcare provider, patient, and family (if applicable) should share in the decision making process.

There are six main types of medications available to treat symptoms of Parkinson disease: levodopa, dopamine agonists (DAs), inhibitors of enzymes that inactivate dopamine (MAO B inhibitors and COMT inhibitors), anticholinergics, and amantadine. Estrogen may be recommended for postmenopausal women with PD.

LEVODOPA

Levodopa is the most effective drug for the treatment of symptoms of Parkinson disease. It is most effective for reducing difficulties moving all or part of the body (akinesia) and rigidity. Tremor is less likely to get better with levodopa, while problems with standing and coordination are even less likely to improve.

There are several formulations of levodopa. In all forms, it is combined in various concentrations with another compound (carbidopa) to improve the efficiency of levodopa and reduce side effects. Carbidopa alone has no benefit.

• In the United States, carbidopa-levodopa is called Sinemet® or Parcopa®. Sinemet® is a pill that is swallowed, while Parcopa® is a tablet that dissolves on the tongue. Carbidopa-levodopa is available in three different quick-acting formulations: 10/100, 25/100 and 25/250 (the numerator is the carbidopa dose in milligrams and the denominator is the levodopa dose). Two slow-release formulations are available: Controlled release carbidopa-levodopa (or CR Sinemet) 25/100 and 50/200.
• In Canada and Europe, levodopa is combined with benserazide (Madopar® or Prolopa®).

Dosing — Treatment is usually started with a small dose of the quick-acting pill two to three times per day with a meal or snack (to minimize nausea, the most common early side effect). The dose is then slowly increased over several days, depending on the person's tolerance, to the lowest dose that controls symptoms. In some cases, a slow-release pill can then be substituted to reduce the number of doses required per day.

Side effects — The most common side effects of levodopa are nausea, sleepiness, dizziness, and headache. More serious side effects can include confusion, hallucinations, delusions, agitation, and psychosis; these are more common in older people. Side effects can usually be avoided or minimized by starting with a low dose and increasing gradually.

Motor complications — In many cases, long-term (5 to 10 years) use of levodopa is associated with complications called motor fluctuations and dyskinesias. Motor fluctuations are a group of symptoms that include the "wearing off" or "on-off" effect (when the medication wears off before the next scheduled dose). Dyskinesias consist of abnormal involuntary movements that cause rapid jerking or slow and extended muscle spasms. Motor fluctuations and dyskinesia develop in at least one-half of people who take levodopa long-term.

For years, there were concerns that levodopa could potentially speed the breakdown and death of dopamine-producing neurons in the brain. However, the evidence is not strong enough to justify avoiding a treatment that is highly effective for most people. As a result, most experts continue to recommend levodopa when symptoms compromise quality of life. Clinical trials are underway to further investigate the benefits versus risks of levodopa. (See 'Clinical trials' below.)

MAO B INHIBITORS

Selegiline (Eldepryl®, Emsam®, Zelapar®) and rasagiline (Azilect®) are monoamine oxidase B (MAO B) inhibitors. These work by blocking the effect of proteins that inactivate dopamine. They are long-acting and modestly reduce symptoms of Parkinson disease. They may help to protect dopamine-producing neurons. However, the benefit is usually small, and some people do not notice any improvement. MAO B inhibitors can be taken alone or in combination with levodopa or other antiparkinson drugs.

Dosing — Selegiline is a pill that is usually taken by mouth once per day (in the morning or at noon to avoid insomnia). Zelapar® dissolves on the tongue. Rasagiline is taken by mouth once per day.

Side effects — Side effects of MAO B inhibitors can include nausea, headache, and difficulty falling asleep. In older people with Parkinson disease, selegiline often causes confusion, which may prevent it from being useful in this group.  People who take antidepressants and MAO B inhibitors at the same time can sometimes develop severe high blood pressure, but fortunately this complication is rare.

Nonspecific MAO inhibitors are sometimes used to treat depression and must not be taken with foods that contain tyramine, such as aged cheeses and red wine. However, selegiline and rasagiline are specific MAO inhibitors, which means that they do not require dietary changes or restrictions.

DOPAMINE AGONISTS

Dopamine agonists (DAs) work by directly stimulating dopamine receptors in the brain. There are several DAs available in the United States, including bromocriptine (Parlodel®), pramipexole (Mirapex®), ropinirole (Requip®), transdermal rotigotine (Neupro®), and apomorphine given by injection (Apokyn®).

Clinical trials have found that dopamine agonists are effective for controlling the symptoms of Parkinson disease. However, they are slightly less effective than levodopa and have more side effects, particularly sedation, swelling of the legs, and visual hallucinations.

Dopamine agonists may be used alone as an initial treatment for some people with early Parkinson disease, especially those who develop symptoms before age 65. In this group, early use of dopamine agonists may postpone the need for levodopa until later in the course of the disease. The use of dopamine agonists rather than levodopa appears to reduce or postpone the onset of motor complications and dyskinesias.

While dopamine agonists may control symptoms in the early stages of the disease, most people with worsening symptoms require levodopa within a few years. In addition, initial symptom control is usually not as good with dopamine agonists as with levodopa. Thus, when deciding which medication to use initially, patients and clinicians must consider the potential benefits of dopamine agonists (fewer levodopa-related motor complications if levodopa can be delayed) as well as the risks (possibly less effective control of Parkinson disease symptoms and more side effects).

Dosing — Dopamine agonists are generally taken by mouth at least three times per day. Apomorphine is only available by injection or continuous IV infusion. Rotigotine (Neupro®) is a dopamine agonist administered with a once daily skin patch.

Side effects — Common side effects of dopamine agonists include sleepiness, nausea, vomiting, low blood pressure after standing up, confusion, hallucinations, and swelling in the lower legs and feet. In some cases, side effects are so bothersome that the person cannot tolerate them. Starting with a low dose and increasing slowly over a period of several weeks may help to minimize side effects.

The manufacturer of pramipexole has issued a warning that "sleep attacks" can occur suddenly and without warning in people who take the medication, particularly when the dose is greater than 1.5 mg/day. Ropinirole probably carries the same risk. People who drive should be aware of this risk and other factors that can increase drowsiness, such as sleep disorders (insomnia, sleep apnea) and certain other medications (sleeping, anxiety medications).

• Dopaminergic dysregulation syndrome — A small number of people with Parkinson disease use levodopa compulsively. Overuse can lead to mood disorders, such as mania (irrational and elevated mood and energy, unusual thoughts). Impulsive behaviors, such as compulsive gambling or sexual behaviors, can also occur. Treatment with antipsychotic medications may be recommended to control these symptoms.
• Impulse control disorders — Treatment with dopamine agonists, even at appropriate doses, increases the risk of impulse control disorders, such as pathologic gambling, compulsive sexual behavior, or compulsive buying. Decreasing or discontinuing the dopamine agonist quickly resolves the behavior in nearly all cases.

COMT INHIBITORS

The catechol-O-methyl transferase (COMT) inhibitors tolcapone (Tasmar®) and entacapone (Comtan®) may be used to prolong and enhance the effect of levodopa. The treatment is primarily used for people with motor fluctuations who have "wearing off" periods at the end of their dose of levodopa. The medication has no effect on its own.

Dosing — Tolcapone is usually taken by mouth three times per day while entacapone is taken with each dose of levodopa, up to eight times per day.

Side effects — The most common side effects of entacapone and tolcapone include dyskinesia, hallucinations, confusion, nausea, diarrhea, orange discoloration of the urine, and low blood pressure after standing up. Tolcapone may increase liver enzymes; blood testing may be recommended to monitor these levels.

ANTICHOLINERGICS

An anticholinergic medication may be recommended to reduce symptoms of bothersome tremor in people with Parkinson disease under age 70 who do not have significant akinesia or difficulty walking. Anticholinergics may be given alone, or with levodopa or dopamine agonists in people with more advanced disease who have a persistent tremor.

There are several anticholinergic drugs available for people with Parkinson disease, including trihexyphenidyl, benztropine, orphenadrine, procyclidine, and biperiden. These medications are believed to be equally effective.

Dosing — Trihexyphenidyl and benztropine are usually taken by mouth two or three times per day.

Side effects — The most common side effects of anticholinergics include dry mouth, blurred vision, constipation, nausea, difficulty emptying the bladder, impaired sweating, and rapid heart rate. Other side effects can be especially bothersome for older adults and anyone with difficulty thinking clearly. These can include difficulty with memory, confusion, and hallucinations.

AMANTADINE

Amantadine (Symmetrel®) is an antiviral drug that was developed to prevent influenza, but was found to improve mild symptoms (tremor, akinesia, rigidity) in people with Parkinson disease. Its benefit appears to be temporary in some people. When combined with levodopa, amantadine may help to reduce motor fluctuations and dyskinesia in people with advanced Parkinson disease.

Amantadine is usually taken by mouth two to three times per day.

Side effects — Possible side effects of amantadine include visual hallucinations and confusion, livedo reticularis (blotchy, purple-colored areas of skin, usually found on the wrists and legs), and swelling of the ankles.

TREATMENT FOR NON-MOTOR SYMPTOMS

Depression — Depression is one of the most common mental health problems experienced by people with Parkinson disease. However, effective medications are available to treat depression. Although the best medication depends upon an individual's situation, a class of medications called SSRIs (selective serotonin reuptake inhibitors) is commonly used. Although less often used, tricyclic antidepressants such as nortriptyline are also effective. The treatment of depression is discussed separately. (See "Patient information: Depression treatment options for adults (Beyond the Basics)".)

Sleep disorders — Daytime sleepiness and fatigue are frequent problems in people with Parkinson disease, and are often a result of nighttime sleeping problems. Treatment options include improving sleep habits, recognizing and treating problems that disrupt sleep (such as pain or the need to urinate frequently), and use of a stimulant (such as caffeine or modafinil) to decrease sleepiness during the day. Other treatments for insomnia are discussed separately. (See "Patient information: Insomnia (Beyond the Basics)".)

Dementia — Difficulties with memory and thinking (dementia) are a common problem for people with Parkinson disease, especially as the disease progresses and the person ages. A class of medications known as cholinesterase inhibitors, which were originally developed to treat Alzheimer disease, may help to improve these symptoms. Examples include rivastigmine (Exelon®), donepezil (Aricept®), galantamine (Razadyne®), and memantine (Namenda®). (See "Patient information: Dementia (including Alzheimer disease) (Beyond the Basics)".)

Psychosis and hallucinations — The treatment of psychosis and hallucinations in people with Parkinson disease often includes stopping or decreasing the dose of one or more of the medications used to treat motor symptoms of Parkinson disease. It is sometimes possible to decrease the dose slightly and improve the symptoms of psychosis and hallucinations with little to no worsening of tremors and other movement problems of Parkinson disease.

If adjusting medications does not improve symptoms adequately, an antipsychotic medication such as quetiapine (Seroquel®) or clozapine (Clozaril®) may be used in low doses. However, people who take clozapine must have frequent blood counts (once per week) due to a potentially serious (but preventable) risk of a drug-induced decrease in the number of white blood cells.

TREATMENT TO SLOW THE PROGRESSION OF PARKINSON DISEASE

There is great interest in finding a treatment that could help to slow the progression of Parkinson disease. The idea is based upon the concept that dopamine-producing neurons could be protected from early death and depletion of dopamine.

No treatment has been proven to be neuroprotective. Many treatments have been studied, including MAO B inhibitors, dopamine agonists, coenzyme Q10, and vitamin E. However, there is not enough evidence to know if these treatments are effective and they are not currently recommended to slow the progression of Parkinson disease. Several clinical trials are underway. (See 'Clinical trials' below.)

CLINICAL TRIALS

Progress in treating Parkinson disease requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

• www.cancer.gov/clinicaltrials/learning/
• www.cancer.gov/clinicaltrials/
• http://clinicaltrials.gov/

SUMMARY

• In most cases, medication for Parkinson disease is recommended once the symptoms are severe enough to interfere with daily living. All decisions regarding the use of antiparkinson medications should be made jointly by the patient, caregivers, family, and the healthcare provider. (See 'When to start Parkinson disease treatment' above.)
• Currently, no treatment has been proven to slow, stop, or change the progression of Parkinson disease. However, medications for Parkinson disease are usually effective in controlling the symptoms of the disease.
• Either levodopa or a dopamine agonist can be used initially for patients who require treatment for symptoms of Parkinson disease. One goal of therapy is try to find the lowest effective dose of medication. It is reasonable to use a dopamine agonist as initial treatment for people with Parkinson disease who are under age 65, and to use levodopa as initial treatment for people age 65 and older. However, there are often exceptions to these general rules, and all treatments should be individualized. Levodopa is the drug of choice if symptoms of Parkinson disease seriously threaten the patient's lifestyle.
• Levodopa is usually taken three times per day, and the dose may be slowly increased over time, depending upon the patient's response. (See 'Levodopa' above.)
• Dopamine agonist medications include bromocriptine (Parlodel®), pramipexole (Mirapex®), ropinirole (Requip®), rotigotine (Neupro®), and apomorphine (Apokyn®). Other PD medications may be taken with a dopamine agonist, if necessary. (See 'Dopamine agonists' above.)
• Selegiline (Symmetrel®) and Rasagiline (Azilect®) are MAO B inhibitors that may help to relieve mild symptoms of Parkinson disease in some people with early Parkinson disease. (See 'MAO B inhibitors' above.)
• Anticholinergic drugs are usually reserved for younger patients in whom tremor is the predominant problem. (See 'Anticholinergics' above.)

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Parkinson disease (The Basics)
Patient information: Medicines for Parkinson disease (The Basics)
Patient information: Tremor (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon

Patient information: Parkinson disease treatment options — education, support, and therapy (Beyond the Basics)
Patient information: Parkinson disease symptoms and diagnosis (Beyond the Basics)
Patient information: Depression treatment options for adults (Beyond the Basics)
Patient information: Insomnia (Beyond the Basics)
Patient information: Dementia (including Alzheimer disease) (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Bradykinetic movement disorders in children
Clinical manifestations of Parkinson disease
Diagnosis of Parkinson disease
Etiology and pathogenesis of Parkinson disease
Management of comorbid problems associated with Parkinson disease
Motor fluctuations and dyskinesia in Parkinson disease
Neuroprotective therapy for Parkinson disease
Nonpharmacologic management of Parkinson disease
Overview of tremor
Parkinson disease dementia
Pharmacologic treatment of Parkinson disease
Surgical treatment of Parkinson disease

The following organizations also provide reliable health information.

• MedlinePlus
• National Parkinson Foundation
• National Institute of Neurological Disorders and stroke
• Parkinson's Disease Foundation
• WE MOVE