Two citizen petitions ask the FDA to add a black box warning to the popular restless legs syndrome drugs.

In 2004, neurologist Daniel Lee, MD, was one of the investigators who declared ropinirole a well-tolerated and effective treatment for restless legs syndrome (RLS), contributing to the US Food and Drug Administration’s (FDA) approval of ropinirole and ushering in an era of dopamine agonists as first-line treatment for RLS.

But now Lee—as well as other prominent sleep physicians—say clinicians and patients must be alerted to the psychiatric serious adverse events that may occur in patients taking dopamine agonists for RLS. Newer studies have found patients being diagnosed with psychiatric illnesses after taking dopamine agonists for RLS, including patients who had no prior psychiatric illness history.

Before dopamine agonists were widely used for RLS, dopaminergic agents such as levodopa were a pharmaceutical of choice. Though both types of drugs impact the neurotransmitter dopamine, the newer dopamine agonists have an affinity for the D3 receptor—a factor in why they are so potent. But because the D3 receptor is also associated with activity, the “acting out” types of psychiatric disorders that some RLS patients have been documented to develop—pathological gambling, hypersexuality, compulsive shopping, bipolar disorders, and substance abuse, to name several that have been recorded—are two sides of the same coin. What makes dopamine agonists so effective also appears to be what may make the drug class activate serious adverse events. “We are opening Pandora’s box,” Lee says.

How did Lee and the original investigative team miss this in the 2004 paper? “In the original study, we only studied about 300 patients and had very strict inclusion and exclusion criteria,” Lee says. “But now in the real world, we can see results from all the patients who have ever been exposed to dopamine agonists.” Lee says he now feels a “moral obligation” to report the findings.

FDA Citizen Petitions

Two FDA citizen petitions requesting a black box warning be added to product labeling for dopamine agonists are currently under review.

The first was filed in June 2016 by a nonprofit health research and advocacy group called Public Citizen.

“The evidence is very strong that dopamine agonists can cause these type of behavior disorders,” says Michael Carome, director of Public Citizen. He points to a recent study, published in JAMA Internal Medicine, which says that the findings “confirm and extend the evidence” that dopamine agonists are associated with impulse control disorders and calls for stronger boxed warnings. “When these behaviors are prolonged, they can destroy the lives of patients,” he says. “It can lead to losing life savings, divorce, and even suicidal thoughts in some patients. We think that, at a minimum, a black box warning should be required for these drugs.”

Carome tells Sleep Review that in December 2016, the FDA sent Public Citizen an interim response, stating a decision has not been reached because it “raises complex issues that require careful analysis and review” by agency officials. “Since that interim response, we have not heard anything. It could take 2 or 3 more years to get a response,” he says.

Carome hopes that a black box warning on dopamine agonists would ultimately keep people healthier and safer. “With stronger warnings, there will be more opportunities for intervention and keeping these side effects from having life-altering consequences,” he says.

The second FDA citizen petition was filed in June 2017 by health economics and outcomes research company BioMedEcon LLC. Although the Public Citizen group’s petition was “beautifully done,” Cheryl Hankin, PhD, owner of BioMedEcon and principal investigator and author of this citizen petition, says she felt it focused primarily on patients taking dopamine agonists for Parkinson’s disease. She wants action and awareness on the serious adverse events being reported by RLS patients too.

“The lore is that because the dopamane agonists used for RLS are at such substantially lower doses than what is used for Parkinson’s, the side effects, which are often psychiatric, don’t occur,” Hankin says. For many years, she adds, “I believed that entirely.”

But when Hankin spent 2 years analyzing RLS patient records contained in a Truven Health database, she was surprised. “I was looking to find what treatments people take, how they fared, and what else they developed….I never intended to find this.” “This” refers to her finding that, compared to dopamine agonist-negative matched controls, dopamine agonist-positive patients were at significantly increased risk for developing new-onset mental disorders during parallel followup periods. These findings were presented as an abstract at SLEEP 2017 (among other conferences) by Hankin, Lee, and additional coauthors and are currently being expounded into a full-length paper that the investigators plan to submit for peer-reviewed journal publication. The dopamine agonist-positive patients “were 2.2 times more likely to have a severe mental illness diagnosis in the 2-year follow up, and 1.9 times more likely to have moderate or mild mental diagnosis,” Hankin says. “Apples to apples as best as we can, we’re finding this consistent, even as we continue to refine. It is compelling and concerning.”

Especially compelling, according to Hankin, is the outcomes were irrespective of a patient’s previous mental disorder history. “The lore also had been if the patient had a history of mental disorder and had restless legs syndrome, you might not consider a dopamine agonist or you might go slow. This study found that irrespective of their mental disorder history, [dopamine agonists] may place patients at risk for new onset mental disorders.” The research was supported by Arbor Pharmaceuticals LLC, makers of Horizant (gabapentin enacarbil), an RLS pharmaceutical that is not in the dopamine agonist class.

GlaxoSmithKline, makers of Requip (ropinirole); UBC, makers of Neupro (rotigotine); and Boehringer Ingelheim Pharmaceuticals, makers of Mirapex (pramipexole) did not respond to Sleep Review‘s interview requests for this article.

Sleep Physician Concern Mounts

Michael H. Silber, MB, ChB, a professor of neurology at the Mayo Clinic College of Medicine and Science, agrees that a black box warning is the right next step in addressing the issue of alerting patients of the risk of developing impulse control disorders. “I would have to see how they worded it, but I don’t think it would be in the least unreasonable to have these warnings in place,” Silber says.

In a 2010 study, published in the journal Sleep, Silber and co-researchers conducted a prospective case-control study on the frequency of impulse control disorders in patients taking dopaminergic agents for RLS. They found that, out of 100 participants, roughly 17% of the RLS treatment group had one or more of the impulse control disorders, which was statistically significant when compared to the control groups who were not taking the drugs. “The frequency was somewhat higher than we predicted considering we use lower doses of these drugs for RLS, compared to the dose for Parkinson’s disease, for example,” Silber says. The conclusion based on this study, and others since, Silber says, has been generally accepted already: this association exists and should be addressed. “The concept of these drugs, in a minority of patients, causing impulse control disorders of varying severity is pretty well accepted today. It’s really a question of the frequency, and I believe 17% is a pretty significant number for physicians to consider,” he says.

Silber adds that these impulse control disorders can be cleared by simply taking patients off the drug. But if the physician isn’t looking for these side effects in their patients, the issue will persist. He says, “The whole point of this is for patients to be aware of the risks when they are put on these drugs, and physicians must question them every time they return since many of these behaviors develop some time after starting the drug.”

Lee and Harkin also say they want physicians, patients, and other stakeholders to be aware of the risks of dopamine agonists for RLS, but they do not seek to make the drug class unavailable. “We need all physicians to be made aware, but the final decision is with the patient and the doctor,” Lee says.

Action Steps

Both FDA citizen petitions are past the online public comments periods, but Hankin says there are still steps concerned clinicians can take.

According to Hankin, action steps include:

  • Neurologists and sleep physicians can get the word out to primary care physicians, who are frequently the clinicians who are managing a patient’s RLS.
  • Monitor carefully all patients who are on dopamine agonists. “Do not assume that a patient who hasn’t had a mental disorder in their past is not susceptible to this serious adverse event,” Hankin says.
  • Professional societies can come forward and make official statements to be clear where they stand on the issue.
  • Ask questions about the existing research and consider doing your own research. “This is very transparent research. So please test it. And add things…think about what more could be done. “

Patients with RLS can suffer severely, Hankin says, citing examples of patients who inadvartantly bruise their own legs in attempts to get the restless sensations to alleviate. “The worst thing of all,” she says “is to add harm to patients who are already suffering.”

Dillon Stickle is associate editor of Sleep Review.

—With reporting by Sree Roy