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Why Study Authors Call for a Black-Box Warning for Dopamine Agonists

ARTICLE IN BRIEF

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Researchers who conducted a review of 10 years of data found that impulse control disorders are associated with dopamine agonists for Parkinson's disease. They called on the Food and Drug Administration to put “black-box” warnings on the medications.

A review of 10 years of adverse drug event reports filed with the U.S. Food and Drug Administration (FDA) found that dopamine receptor agonist drugs are associated with troubling behavioral changes, including gambling, compulsive shopping, and an obsession with sex.

The researchers who conducted the review said physicians who prescribe dopamine receptor agonist drugs should counsel patients and their families that they may start acting in compulsive and reckless ways, and monitor patients for signs of bizarre behavior. They also said the FDA should require “black-box” warnings on the medicines.

“At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings about the potential for development of severe impulse control disorders as part of their prescribing information,” the researchers reported in the Oct. 20 online edition of JAMA Internal Medicine. “Our data, and data from prior studies, show the need for these prominent warnings.”

Previous studies, including case reports and small cohort studies, have raised red flags about the potential for severe impulse control disorders in patients taking dopamine receptor agonists. The drugs, mostly used in Parkinson's patients, are also prescribed for restless legs syndrome and hyperprolactinemia.

“The events typically involve behaviors such as pathological gambling, hypersexuality, compulsive shopping, and less frequently, binge eating and punding (the compulsive fascination with and performance of repetitive mechanical tasks). They can have catastrophic effects on jobs, marriages, and family finances,” wrote the research team headed by Thomas J. Moore, a senior scientist with the Institute for Safe Medication Practices, based in Horsham, PA.

While estimates vary on how common severe impulse control disorders are in patients who take dopamine receptor agonist drugs, Moore told Neurology Today that it is thought that about 10 to 15 percent of patients on the drugs experience some variation of the problem. The odd behavior usually subsides when patients stop taking the drugs. Moore noted that other drugs such as selective serotonin reuptake inhibitors (antidepressants) carry black-box warnings about suicidal behaviors, even though severe side effects related to those drugs appear to be less common.

When it comes to dopamine agonists, “We're fairly certain that these problems may be seriously underreported,” he said. “For one thing, they can be embarrassing, and in addition, patients and families may not make the connection between the behavior and the drug.”

Dopamine receptor agonist drugs are widely prescribed, accounting for 2.1 million dispensed outpatient prescriptions in the fourth quarter of 2012, according to the study.

STUDY METHODOLOGY, RESULTS

The analysis involved a review of 2.7 million serious domestic and foreign adverse drug event reports between 2003 and 2012 from the FDA Adverse Event Reporting System. The researchers searched for cases that included references to 10 specific medical terms that described these unusual impulse control disorders. They identified 1,580 cases: 710 for dopamine receptor agonists (six different medications) and 870 for other drugs. They then calculated the “proportional reporting ratio,” or PRR, to determine whether the proportion of adverse event reports involving impulsive behavior was higher for dopamine receptor agonists compared with all other drugs, a concept similar to relative risk. They calculated a PRR of 277 for the dopamine agonist drugs, meaning that the number of reports was nearly 300 times higher than expected if such events occurred by chance.

The association was strongest for pramipexole and ropinirole, which have an affinity for the dopamine D3 receptor. The association was not as strong for four other drugs that are less selective agonists — cabergoline, bromocriptine, rotigotine, and apomorphine.

GAMBLING MOST COMMON CONCERN

The review found that gambling was the most common impulsive behavior reported, followed by hypersexuality, compulsive shopping, and poriomania (wandering away from home). In 61.7 percent of cases involving dopamine receptor agonists, the drugs had been prescribed for Parkinson's disease. Due to limitations on the information contained in the FDA database, the study could not address whether the impulsive behaviors were linked to higher doses of the drugs or whether they occurred among patients with certain characteristics.

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THOMAS J. MOORE said that while estimates vary on how common severe impulse control disorders are in patients who take dopamine receptor agonist drugs, it is thought that about 10 to 15 percent of patients on the drugs experience some variation of the problem. The odd behavior usually subsides when patients stop taking the drugs.

An accompanying editorial by Howard Weiss, MD, of Sinai Hospital of Baltimore and Johns Hopkins University, and Gregory Pontone, MD, of Johns Hopkins University School of Medicine, noted that the study raised some important questions. Among them: “How do dopamine receptor agonist drugs trigger the abnormal behaviors seen in patients with impulse control disorders? Why do some patients, but not others, develop these problems?

“Impulse control disorders triggered by dopamine receptor agonist drugs could be viewed as excessive stimulation of D3 receptors,” they wrote. “Increased D2 and D3 receptor agonism could, in effect, ‘release the brake’ on brain mechanisms that would normally inhibit risky behaviors while simultaneously invigorating reward-seeking behaviors.”

DRUGS ARE OVER-PROMOTED

Drs. Weiss and Pontone said dopamine receptor agonists have been promoted as first-line treatments for Parkinson's patients. They noted that “a recent large, open-label, pragmatic randomized trial shows carbidopa/levodopa and not dopamine receptor agonist drugs to be the safest and most effective initial treatment for Parkinson disease regardless of the patient's age.” The study was published in a June 11, 2014 online edition of The Lancet. [Read the Neurology Today story here:.]

“Physicians have overestimated the benefit and underestimated the risk associated with the use of dopamine receptor agonist drugs,” they wrote.

Concerns about the drugs are not new. Mark Stacy, MD, a professor of neurology and vice dean for clinical research at Duke University, published an article in Neurology in 2003 on the connection between dopamine agonists and gambling after he started hearing stories of impulsive behavior from the families of his Parkinson's patients. At the time, he was practicing in Phoenix, Arizona, where many retirees like to go on bus outings to nearby casinos.

Dr. Stacy said that one day, a patient's wife told him, “Doctor, since the last time he saw you, he lost $60,000 in a gambling casino.” Just a few days later, he heard a nearly identical story from the spouse of another patient. Dr. Stacy conducted a review of a large database of Parkinson's patients and found more cases of impulsive gambling.

Dr. Stacy said the impulsive behavior often starts a considerable time after patients start taking the drugs or when a dose gets increased.

“It's like a switch gets flipped,” he said, and all of a sudden a Parkinson's patient may be mowing the lawn incessantly, gardening morning and night, or taking apart and reassembling a clock radio over and over again.

SHOULD THE DRUGS BE PRESCRIBED?

Dr. Stacy told Neurology Today that he hasn't backed off from using dopamine receptor agonists “because they are absolutely essential to mobility in many patients,” but he has become more judicious with dosing. He said he aims to prescribe just enough of a drug to improve motor symptoms in his Parkinson's patients, and rather than escalating dosing he may refer certain patients earlier for deep brain stimulation.

“Dopamine agonists and levodopa are the drugs of choice for people with motor symptoms of PD, including tremor, bradykinesia, and rigidity,” Dr. Stacy said. “For patients requiring treatment who are younger than 60, I will usually begin with a dopamine agonist and add levodopa when symptoms are no longer adequately controlled with modest doses. While I do not think there are absolute contra-indications to prescribing dopamine agonists, I am more careful to address risk factors of impulse control disorders, such as a history of drug or alcohol dependence, suicide, major depression, or a family history of these symptoms.”

Janis Miyasaki, MD, an associate professor of neurology at the University of Alberta in Canada, said that regardless of whether dopamine receptor agonists eventually carry a black-box warning, it's the responsibility of prescribing doctors to make sure their patients are helped, not hurt, by the drugs. She said physicians need to be direct and specific with patients and their families about the potential for serious changes in behavior, which might not always be so obvious to family members. Unbeknownst to a spouse, for instance, a patient may take out new credit cards and rack up thousands of dollars in debt.

“It might be that you can't go by a corner store without going in to buy lottery tickets. They seem to have a compulsive need to take on risk,” she said. Dr. Miyasaki said Parkinson's patients often have little insight into their behavior, making it all the more critical that families be alert to sudden changes in routine or secretive behavior before there are devastating consequences.

She said it is good practice to screen patients before prescribing the drugs to pinpoint people who may not be good candidates because they already have tendencies toward obsessive and compulsive behavior or have a personal or family history of addiction. The Disease Impulsive-Compulsive Disorders Questionnaire (QUIP) is used to detect the development of abnormal behaviors in Parkinson's patients, she said.

“Dopamine agonists have a very important place in treating Parkinson's disease,” whether alone or in combination with levodopa, Dr. Miyasaki said. But she, too, tries to use as low a dose as possible in her patients. She said it would be unfortunate if patients and their families were scared away from medicines that can allow them better movement and function.

The decision to prescribe dopamine agonists is complex, she noted, adding that it is a matter of balancing individual patient profiles and needs. Dopamine agonists should only be used with extreme caution when there is cognitive decline, orthostatic hypotension that is refractory to treatment, hallucinations, a personal or family history of substance abuse or addictive behaviors, and pre-existing daytime sleepiness.

“Presenting patients and their caregivers with the information and options and allowing them to make a choice is important in this condition,” Dr. Miyasaki said.

“When presented with the information and potential risks of each class of drug, levodopa and dopamine agonists, patients have their own personal reasons for choosing one over the other,” she continued. “One patient may have a goal of remaining dyskinesia-free, and therefore the dopamine agonist first would be appropriate, while another patient may want rapid onset of benefit and low risk of sleepiness, making levodopa the preferred agent. We need to help our patients achieve the highest quality of life possible.”

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DR. MARK STACY said he hasnt backed off from using dopamine receptor agonists “because they are absolutely essential to mobility in many patients,” but he has become more judicious with dosing. He said he aims to prescribe just enough of a drug to improve motor symptoms, and rather than escalating dosing he may refer certain patients earlier for deep brain stimulation.

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DR. JANIS MIYASAKI said it is good practice to screen patients before prescribing the drugs to pinpoint people who may not be good candidates because they already have tendencies toward obsessive and compulsive behavior or have a personal or family history of addiction.

LINK UP FOR MORE INFORMATION:

•. Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern Med 2014; Epub 2014 Oct. 20.
    •. Gagne JJ. Finding meaningful patterns in adverse drug event reports. JAMA Intern Med 2014; Epub 2014 Oct. 20.
      •. Weiss HD, Pontone GM. Dopamine receptor agonist drugs and impulse control disorders. JAMA Intern 2014; Epub 2014 Oct. 20.
        •. PD Med Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomized trial. Lancet 2014; Epub 2014 June 11.
          •. Neurology Today articles on dopamine agonists: