Serious Impulse Control Disorders With Dopamine Agonists

Pauline Anderson

October 20, 2014

Researchers have again linked pathologic gambling, compulsive shopping, and other impulse control disorders with dopamine receptor agonist drugs, such as pramipexole and ropinirole.

This time, they found that these drugs had a strong signal associated with reports of impulse control disorders that were uncovered over a 10-year period.

"Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with serious impulse control disorders; the associations were significant, the magnitude of the effects was large, and the effects were seen for all 6 dopamine receptor agonist drugs," the authors, led by Thomas Moore, AB, senior scientist, Drug Safety and Policy, Institute for Safe Medication Practices, Alexandria, Virginia, conclude.

The study was published online October 20 in JAMA Internal Medicine.

The study used adverse drug event reports entered into the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from 2003 to 2012. Of the 1580 reports of impulse control disorders from the United States and 21 other countries, gambling was the most frequent behavior, reported (39.7%), followed by hypersexuality (29.4%), compulsive shopping (12.8%), and poriomania (the morbid impulse to wander away from home [7.9%]).

Dopamine receptor agonist drugs were involved in 44.9% of the reported impulse control disorder events. These drugs had been prescribed for Parkinson's disease in 61.7% of events, restless legs syndrome in 23.8%, and conditions associated with hyperprolactinemia in 3.5%.

To assess the association between impulse control disorder cases and each specific suspect drug, researchers calculated the proportional reporting ratio (PRR), a ratio similar in concept to the relative risk ratio.

The study found that the 6 dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR, 277.6; P < .001). There was a stronger signal for agents with a preferential affinity for the dopamine D3 receptor, notably pramipexole (n = 410; PRR, 455.9; P < .001) and ropinirole (n = 188; PRR, 152.5; P < .001).

They also found a weaker signal for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor.

"The signal for dopamine receptor agonist drugs with preferential affinity for the D3 receptor, a molecule target that is also under study for potential treatments of addiction, was markedly stronger than the signal for the less selective agonists," they write.

The authors investigated whether some external event, media publicity, or litigation might have stimulated an unusual number of reports. They concluded that because reports from both inside and outside the United States have grown during the decade studied, "it is unlikely that a spurt of publicity or specific events explained our findings."

While none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings about the potential for severe impulse control disorders, the new data support the need for these prominent warnings, said the authors. "Physicians who prescribe dopamine agonists should also vigilantly monitor their patients and ensure that patients, families, and caregivers are counseled about the risk of these serious adverse events."

Warn Patients

The authors of an invited commentary agreed. Before prescribing these drugs, doctors should warn patients and families or caregivers of the potential for triggering uncontrollable or excessive behavioral addictions, write Howard Weiss, MD, Department of Neurology and Neurological Sciences, and Gregory Pontone, MD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland.

After initiating treatment, physicians should regularly query patients about conduct that could indicate development of an impulse control disorder, they said.

Dopamine receptor agonist drugs should not be prescribed in patients with a personal or family history of obsessive-compulsive disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors, they added.

It's not surprising that it took many years before impulse control disorders were recognized as a complication of dopamine receptor agonists, write Dr Weiss and Dr Pontone.

In our view, these medications should be used less frequently and with great caution, paying close attention to possible untoward effects on behavior and impulse control. Dr Howard Weiss and Dr Gregory Pontone

"Patients and health care professionals are traditionally accustomed to inquiring about 'typical' medication adverse effects such as dizziness, rash, or nausea, but less likely to appreciate the role of medications in altering behavior," they write. "During an office visit, a patient is unlikely to spontaneously mention, 'By the way, doctor, I lost $250 000 in casinos last year, and I purchase $500 of lottery tickets every week,' or 'I spend all night on Internet pornography sites and am soliciting prostitutes.'"

Physicians have not only underestimated the risks associated with these drugs but also overestimated their benefit, the editorialists conclude. "In our view, these medications should be used less frequently and with great caution, paying close attention to possible untoward effects on behavior and impulse control."

Study Limitations

In another invited commentary, Joshua Gagne, PharmD, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, outlined several limitations of FAERS. These include under-reporting and a lack of information on the number and characteristics of patients for whom the drug was prescribed.

Given these limitations and the "provocative" new analysis, the question is whether the association between dopamine receptor agonist drugs and impulse control disorders is a true causal connection or merely a pattern among random data, said Dr Gagne.

"With the large PRR that may actually be attenuated by confounding and the emerging evidence from other sources, the likelihood of a causal connection is high," he concludes.

Dr Moore has been a consultant or expert witness in civil and criminal litigation involving many psychiatric drugs and psychiatric adverse drug effects. None of this litigation has involved the 6 dopamine receptor agonist drugs that are primarily discussed in his article. The other authors have disclosed no relevant financial relationships.

JAMA Intern Med. Published online October 20, 2014. Abstract Weiss/Pontone Editorial Gagne Editorial


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