How Do Parkinson’s Meds Work?

It’s all about the dopamine.

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On Monday, Rush Limbaugh claimed that Michael J. Fox had exaggerated the symptoms of his Parkinson’s disease in a series of campaign ads. “Either he didn’t take his medication, or he’s acting,” said Limbaugh. The next day, Fox pointed out that the medications have different effects on different days: “It’s ironic,” he said, “my pills are working really well right now.” And on Wednesday, Slate’s Timothy Noah pointed out that the medications for Parkinson’s can actually cause their own symptoms. How do Parkinson’s meds work?

They beef up your brain’s supply of dopamine. Parkinson’s disease results from the death of dopamine-producing neurons in a part of the brain called the substantia nigra, which helps to control the motor system. When enough of these cells die off, patients can develop the three classic symptoms of Parkinson’s: tremors, rigidity, and slowness of movement. (James Parkinson’s paper from 1817 described an “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses being uninjured.”)

To treat the disease, doctors most often prescribe levodopa—a precursor to dopamine that can make its way from the bloodstream to the substantia nigra. (Regular dopamine would get blocked by the blood-brain barrier.) Once there, the levodopa gets converted into dopamine and reverses the classic symptoms. About three-quarters of all treated Parkinson’s patients get the drug; most also use additional treatments that make levodopa more effective. For example, COMT inhibitors help to keep levodopa from being converted into dopamine before it can reach the brain.

Not everyone responds to levodopa in the same way, and not every dose has the same effect. (Thus Fox’s observation that “my pills are working really well right now.”) The effects of levodopa also change over time. Repeated doses of the drug change the properties of the cells that respond to dopamine—they get accustomed to short bursts, rather than a steady supply, and they start to become hypersensitive. As a result, the levodopa begins to push a patient who can’t move too much in the other direction; he’ll start making large, involuntary movements. This condition—called dyskinesia—occurs in about a third of the people who take the drug and generally kicks in after a few years’ worth of treatment.

The swaying and head-rolling on display in the Fox campaign ads could be standard “peak-dose” dyskinesia. (Click here to watch the ad.) That means the symptoms kick in as levodopa reaches its highest levels in the blood—starting about 45 minutes after it’s taken—and then subsides before the next dose. Fox has had Parkinson’s for more than a decade, and according to Dr. Eric Molho of Albany Medical Center’s Parkinson’s Disease and Movement Disorders Center, he appears to suffer from drug-induced dyskinesia of moderate intensity.

In late stages of Parkinson’s, the levodopa can also produce an “on/off” response. As more cells in the substantia nigra die off, the brain becomes less able to store dopamine, and each dose of the drug lasts for a shorter time. In some cases, the effects can disappear within a matter of minutes.

Long-term patients often have to manipulate the size and schedule of their doses so as to minimize both the dyskinesia and the on/off response.

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Explainer thanks Dr. Eric Molho of Albany Medical Center.