ARTICLE IN BRIEF
A longitudinal analysis found that the use of dopamine agonists for Parkinson's disease is associated with a much higher risk of impulse control disorders than previously thought.
Patients taking dopamine agonists for Parkinson's disease (PD) have a much higher incidence of impulse control disorders (ICDs) than previously reported. In patients without ICDs at baseline, the cumulative incidence over five years was nearly 50 percent, the study authors reported in a paper published in the online June 20 edition of Neurology.
“Thanks to our longitudinal and prospective design, we could estimate the incidence of ICDs in more than 400 patients over five years,” Jean-Christophe Corvol, MD, PhD, lead investigator and assistant professor in neuro-pharmacology at the Pitié-Salpêtrière Hospital in Paris, told Neurology Today in an email. “Our results are higher than the prevalence rates of 10 to 20 percent reported in cross-sectional studies and are consistent with the Parkinson's Progression Markers Initiative (PPMI) cohort study which showed a cumulative ICD incidence of 25 percent.”
Because it's hard to predict who will develop ICDs, which can cause financial, legal or psychosocial problems, Dr. Corvol recommended that neurologists “inform patients about the risk of ICDs before starting therapy and regularly during follow-up. Neurologists should also carefully and systematically monitor patients for ICDs throughout the duration of the disease.”
STUDY DESIGN
The researchers analyzed data from the Drug Interaction with Genes in Parkinson's disease, an ongoing longitudinal cohort study led by Dr. Corvol, which was sponsored by the Assistance Publique Hopitaux de Paris. The 426 patients were recruited from four French university hospitals and four general hospitals from 2009 to 2013. The 411 patients included in the study had Parkinson's disease for five years or less.
The patients (40.6 percent women, mean age 62.3 years) were assessed at baseline and then annually for up to five years for PD and ICDs (compulsive gambling, eating, buying, sexual behavior, hobbyism, and hypercreativity), and their use of antiparkinsonian drugs.
The researchers analyzed associations between incident and prevalence rates of ICDs and dopamine agonist use in the past 12 months, from disease onset through follow-up period (ever users), and for cumulative duration and cumulative dose (at each visit).
Three-hundred fifty-six of the 411 patients were ever users and 80 percent of them did not have ICDs at baseline. The five-year cumulative incidence of new onset ICDs was 46.1 percent [95% CI 37.4-55.7]; 51.5 percent [95% CI 41.8-62.1] in ever users, and 12.4 percent [95% CI 4.8-30.0] in never users.
When researchers examined the relationship between daily dose of dopamine agonists and ICDs, they found “up to 200 mg of levodopa equivalent (2 mg of pramipexole, 10 mg of ropinirole) increased the risk for ICDs. However, because both longer duration and cumulative dose are high risk factors for ICDs, a low dose for a long duration and high dose for a short duration both increase the risk of developing ICDs,” said Dr. Corvol.
During sensitivity analyses, higher prevalence rates of ICDs had a stronger association with pramipexole and ropinirole alone and in combination than with other types of dopamine agonists.
There was no difference in rates of ICDs between standard and extended release forms of dopamine agonists. Similar analyses for levodopa and other antiparkinsonian drugs did not show a strong association with ICDs. After dopamine agonists were discontinued in patients with ICDs, they progressively resolved.
“A limitation of this study is the relatively young population, and the high rate of patients treated with dopamine agonists (86 percent), which may over-estimate the incidence in a general population. In addition, the study started in 2009, and neurologists have become more aware of these adverse effects and may use lower doses of dopamine agonists,” said Dr. Corvol.
EXPERT COMMENTARY
“This is only one of a few studies to look at the incidence of ICDs with Parkinson's disease; all other studies have looked at prevalence. It replicates findings from my prior study, but in a much larger multi-center cohort,” said Melissa Nirenberg, MD, PhD, FAAN, a movement disorders specialist and chief medical officer of the New York Stem Cell Foundation Research Institute in New York City, who was not involved in the study. Her paper was published in the March 2013 edition of Movement Disorders.
“This study provides more evidence to suggest that the use of dopamine agonists should be limited in clinical practice. Because of the high risk of ICDs and their consequences, I am hesitant to initiate dopamine agonist therapy,” said Dr. Nirenberg.
“Providers should be cautioned that impulse control disorders are a class effect of dopamine agonists, and are not specific to Parkinson's disease,” Dr. Nirenberg added. “They have been observed when dopamine agonists are used — even at low doses — for a variety of other indications, including restless legs syndrome, atypical parkinsonism, fibromyalgia, and pituitary adenoma.”
Dr. Nirenberg referred to levodopa “as the most effective medication to treat Parkinson's disease with the least side-effects. ‘Levodopa-sparing’ strategies [alternatives to levodopa such as dopamine agonists or monoamine oxidase type B inhibitors] do not improve outcomes and can cause significant side-effects and other secondary consequences.”
However, discontinuing dopamine agonists can be difficult in patients experiencing severe withdrawal symptoms, such as anxiety, depression, agitation, suicidal ideation, fatigue, orthostatic hypotension, nausea, and vomiting, according to her paper published in the January 2010 edition of JAMA Neurology.
“My practice is to taper off patients on dopamine agonists very slowly at the first sign of ICDs, and to communicate frequently with patients and caregivers during the tapering process,” said Dr. Nirenberg.
Although fewer neurologists are prescribing dopamine agonists, “these medications are quite effective and shouldn't be avoided,” said Daniel Weintraub, MD, professor of psychiatry and neurology at Perelman School of Medicine, University of Pennsylvania in Philadelphia.
“Educating patients about ICDs and being vigilant are critical to early detection and adjusting the drug therapy including decreasing the dose or trying different formulations such as the transdermal patch or extended release,” said Dr. Weintraub. He explained that a moderate dose of pramipexole is 3 mg daily and patients can take 0.5 mg of the drug three times daily and still obtain motor benefits.
Levodopa can be the initial treatment with or without monoamine oxidase type B inhibitors, added Dr. Weintraub. However, because levodopa has been associated with inducing dyskinesias, he noted that a study published in the October 2014 edition of Brain, showed that the duration of levodopa treatment may be less important than disease duration or levodopa dose.
Physicians may also be prescribing fewer dopamine agonists due to the recent focus on patient-centered decision making. “Movement disorders specialists now give patients more information about treatment options so that patients can weigh all the potential complications: cognitive, non-motor and motor,” said Janis Miyasaki, MD, MEd, FRCPC, FAAN, director of the Parkinson and Movement Disorders Program at the University of Alberta in Edmonton Canada.
While movement disorders specialists tend to focus on motor outcomes, patients may have different priorities. “For example, younger patients may still be working and the risk of impulsive decision-making could be devastating especially in certain professions such as banking or aviation. Patients need to be aware of the potential risk so that they can make informed decisions,” said Dr. Miyasaki.
She noted that the researchers didn't assess whether the participants had a personal or familial risk of ICDs. “We found that a personal or family history of addictive behaviors including substance abuse increased the risk of ICDs,” said Dr. Miyasaki, who co-authored a paper published in the February 2007 edition of Archives of Neurology.
Another study limitation was the lack of a standardized tool to detect and assess ICDs. Dr. Miyasaki, who participated in a validation study of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP) published in the July 30, 2009 edition of Movement Disorders, said: “Our self-assessment tool detected ICDs and their severity as well as subsyndromal disorders that didn't meet the full ICD diagnostic criteria but still can cause some behavioral problems. The ideal time for physicians to act is before a patient develops an addiction or compulsion with serious negative consequences.”
LINK UP FOR MORE INFORMATION:
•. Corvol JC, Artaud F, Cormier-Dequaire F, et al Longitudinal analysis of impulse control disorders in Parkinson disease http://n.neurology.org/content/91/3/e189. Neurology 2018; Epub 2018 Jun 18.
•. Bastiaens J, Dorfman BJ, Christos PJ, et al Prospective cohort study of impulse control disorders in Parkinson's disease https://onlinelibrary.wiley.com/doi/full/10.1002/mds.25291. Mov Disord 2013; 28(3): 327–333.
•. Kraemmer J, Smith K, Weintraub D, et al Clinical-genetic model predicts incident impulse control disorders in Parkinson's disease https://jnnp.bmj.com/content/87/10/1106. J Neurol Neurosurg Psychiatry 2016; 87(10): 1106–11.
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