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Published: January 14, 2019

A class of drugs called dopamine agonists, used mainly to treat Parkinson’s disease, has long been suspected of causing strange psychological side effects, such as compulsive gambling and sexual activity. But a meta-analysis published today in JAMA Internal Medicine aims to settle the question and change the way doctors, patients, and regulators handle the drugs.

The analysis of adverse events reported to the Food and Drug Administration over a 10-year period linked the drugs to excessive gambling and sexual behaviors, but also to shopping sprees, stealing, and binge eating. More incidents stemmed from the use of pramipexole and ropinirole than from other drugs in the class. 

“As a paper it really isn’t telling us anything we didn’t know, it’s just reinforcing it. But it needs reinforcing because most physicians aren’t aware of the problem or underestimate the severity,” said Dr. Howard Weiss, an associate professor of neurology at Johns Hopkins University, who published a commentary that accompanies the study.

Dopamine receptor agonists were prescribed 2.1 million times in the last four months of 2012 alone. The drugs are a second-line treatment for Parkinson’s disease, after the dopamine replacement drugs levodopa and carbidopa. Dopamine agonists are also prescribed for other conditions, including restless leg syndrome and the hormonal condition hyperprolactinemia.

As many as 1 in 7 patients who take dopamine agonists experience psychological side effects, the analysis suggests.

“That is a striking psychological side effect rate,” said study author Thomas Moore, a drug safety researcher at the Institute for Safe Medication Practices. “There are a lot of forms of impulse control, but this is a striking and unusual list” of behaviors.

Joshua Gagne, a pharmacoepidemiologist at Harvard Medical School who evaluated the statistics in a note that ran alongside Moore’s analysis, called the number of reported incidents “eyebrow raising.”

“It’s rare that we see such large measures of association,” he said.

‘The Tip of the Iceberg’

Reported side effects may be a low estimate of problem behaviors if patients are embarrassed to admit them to their doctors or never think to associate them with their medications, experts said.

“I think we’re only seeing the tip of the iceberg,” said Weiss. “When doctors ask, ‘Are you having any side effects from the drugs?,’ nobody’s going to ask, ‘Are you going to casinos?’”

Silence about the side effects can make them worse. Patients may develop gambling habits that go undetected until they’ve gambled away their homes or life savings. They may say they’re going to work when they’re actually going to casinos, Weiss said.

Experts hope that by educating patients about potential behavioral side effects of the drugs, patients will be more willing to tell their health care providers about changes in their behavior.

“Hopefully it opens up a conversation about the fact that drugs in some people can have striking and destructive effects on behavior,” said Moore.

Shifting the Risk/Benefit Equation

If the use of dopamine receptor agonists to treat Parkinson’s disease raises such serious concerns, where does that leave patients suffering from restless leg syndrome or hyperprolactinemia?

“There may be a risk that’s associated [with the drugs] regardless of what they’re being used for, but the severity of that risk may weigh differently for different conditions,” Gagne said.

“I would never use those drugs for restless leg syndrome,” said Weiss. But there are other drug options to treat that condition.

Parkinson’s disease is serious and degenerative, so the drug risks may present a reasonable tradeoff for many patients with that disease.

Even so, as they fully recognize the side effects of these drugs, doctors may return to prescribing the older drugs levodopa and carbidopa more frequently, Weiss said.

“Carbidopa/levodopa is the safest and best option for vast majority of Parkinson’s patients,” he said.

A series of studies, many funded by the makers of dopamine agonists, had questioned the safety of levodopa and carbidopa. Though none found serious problems, some physicians became skeptical enough to shy away from the drugs.

Emerging treatments for Parkinson’s disease, such as the promising use of electrical stimulation of the brain, could make drug side effects a problem of the past. 

The FDA may also attach a more serious warning to dopamine agonists, perhaps even its most severe warning, known as a “black box warning.”

“When you see a black box warning you know there’s a serious problem. And these effects do warrant that type of warning,” Weiss said.


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