Treatments for Parkinson's disease (PD) can be very effective, but they all produce side effects, leaving patients and their doctors wondering which drug or combination of drugs will work the best.

Now a large study comparing the three leading treatments shows the oldest to be the best—but not by a large margin—which leaves plenty of reasons to keep using the more recently developed alternatives. The results were published in the June 11 online edition of the journal The Lancet.

Without treatment, PD eventually becomes disabling. People first develop a slight tremor, usually in a finger or a hand, or twitching in the arms or legs. Then they start to feel as though their feet are stuck to the floor when they try to take a step.

All of these problems result from the death of cells that are located deep within the brain. Those cells produce dopamine, a brain chemical (neurotransmitter) essential for normal muscle movement. When the level of dopamine in the brain drops below a certain level, symptoms emerge and, without treatment, they worsen, making walking and other simple daily activities like drinking a cup of coffee difficult. [See "Parkinson's Disease: The Basics."]

Fortunately, since the 1960s, people with PD have been able to take levodopa, which nerve cells in the brain use to make dopamine, and reverse most of the symptoms for a few hours.

Unfortunately, people who have been on the drug for a few years often develop unwanted side effects—for example, movements known as dyskinesias, which cause them to rock and gesture erratically and display unintended facial expressions. In addition, the effects of levodopa may change, with the drug becoming ineffective at times.

Over the years other types of drugs have been developed to replace levodopa. Dopamine agonists, for example, stimulate receptors in the brain and mimic the action of dopamine even when none is present. They include pramipexole (brand name Mirapex), ropinirole (brand name Requip), and rotigotine (brand name Neupro).

Another drug class known as monoamine oxidase-B (MAO-B) inhibitors block the enzyme that breaks down dopamine in the brain, which helps to keep dopamine levels elevated. Rasagiline (brand name Azilect) and selegiline (brand name Anipryl) are both MAO-B inhibitors.

Today, people with PD can achieve relief by taking one or more of these drugs; though levodopa is widely regarded as the most effective for treating movement problems. However, because its side effects often grow worse over time, levodopa is considered a questionable choice for patients diagnosed with PD before age 60.

"With young-onset PD patients it's prudent to spare them from levodopa early on because they are going to be committed to it for many decades," says Joseph Jankovic, MD, a professor of neurology and director of the Parkinson's Disease Center and Movement Disorders Clinic at the Baylor College of Medicine in Houston, who is a Fellow of the American Academy of Neurology (FAAN).

The possibility of long-term side effects from levodopa combined with intensive marketing by the makers of alternative medications has instilled in some doctors "levodopa phobia"—the fear of prescribing the drug early in the course of PD. The new study, known as PD MED, should put to rest such overblown and potentially unwarranted fears of the drug, says study leader Richard Gray, a professor at the University of Oxford in England.

"The PD MED trial was the largest ever conducted of PD treatments, so its results can be trusted," says Gray. "Although the differences in favor of levodopa are small, when you consider the short- and long-term benefits, side effects, quality of life for patients, and costs, the old drug levodopa is still the best initial treatment strategy for most patients."

That doesn't mean levodopa is right for every patient, Gray adds.

"Levodopa is the best first option for most patients, but starting a patient with an MAO-B inhibitor and adding levodopa as needed is another reasonable option," he says. "In current practice, most patients younger than the age of 70 are treated initially with a dopamine agonist to avoid levodopa-related motor complications, but dopamine agonists are the most expensive treatment option and their results were not as good in our study."

The PD MED trial divided 1,620 patients into three groups to receive levodopa, an MAO-B inhibitor, or a dopamine agonist. The patients were asked to assess how much difficulty they were having with the challenges common to patients with PD, such as walking, eating, bathing, shopping, remembering, and coping with anxiety.

There were not major clinical differences between the three types of therapies on tests designed to measure the severity of a patient's symptoms.

However, only 2 percent of the patients taking levodopa stopped treatment due to side effects, while 28 percent of those taking a dopamine agonist and 23 percent taking a MAO-B inhibitor stopped treatment due to nausea, sleep disturbances, and other problems.

Cynthia Comella, MD, FAAN, a professor of neurological sciences at Rush University Medical Center in Chicago was surprised that the difference between the three drugs was not more robust.

Still, Dr. Comella believes all three classes of drugs will continue to be used. "This does not change clinical practice for me, and I certainly don't think everyone should abandon the agonists and MAO inhibitors based on these results," she says. "To eliminate these medications would limit the choice of therapy for the individual patient and do a disservice to the Parkinson's population."

Charles H. Adler, MD, PhD, FAAN, a professor of neurology at the Mayo Clinic College of Medicine in Scottsdale, AZ, agrees. "Both the dopamine agonists and MAO-B inhibitors are effective medications used as adjuncts to levodopa," he says. "Physicians will need to weigh benefits and side effects for each patient individually."

Dopamine agonists and MAO-B inhibitors delay the onset of dyskinesias, but levodopa is clearly the most effective drug for PD in terms of controlling symptoms, says Stephen G. Reich, MD, the Frederick Henry Prince Distinguished Professor in Neurology at the University of Maryland School of Medicine.

"None of the other medications provide the same degree of symptoms control, and they're generally less well tolerated," he points out. "I tend to use levodopa as the initial therapy for most of my patients."

Still, when early symptoms are mild, they probably can be controlled sufficiently with an MAO-B inhibitor or a dopamine agonist, Dr. Reich adds.

"Young patients seem to be more sensitive to levodopa-induced fluctuations, so they might be better candidates for initiating treatment with a dopamine agonist or MAO-B inhibitor," he says. "On the other hand, young patients are typically in the work force, often at the prime of their careers, and often have children at home, which necessitates the most efficacious medications for PD, and that is levodopa. So I have no hesitancy in using levodopa as initial therapy for someone with young-onset PD."

Dr. Jankovic agrees that neurologists must consider the details of each patient's case before deciding on how to treat PD.

"Therapy has to be individualized," he says. "If a patient with early onset PD has mild symptoms—a slight tremor in the right thumb that isn't troublesome, for example—then it would be reasonable to consider an MAO-B inhibitor or a dopamine agonist, or a combination of the two, before going to levodopa. On other hand, if a young-onset patient has troublesome symptoms that could put his or her job in jeopardy, levodopa might be considered the first treatment. Treatment has to be tailored to the needs of each patient."

For More Information on Parkinson's Disease

• Check out our coverage in Neurology Now
• Read about the latest PD advances in Neurology Today
• Visit Patient Pages on PD (and other conditions) from Neurology, one of the American Academy of Neurology's medical journals
• Watch a free guide about Parkinson's disease on the AAN YouTube Channel
• Read Navigating Life with Parkinson's Disease from the Neurology Now Book series