By Claire Henchcliffe, MD, PhD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is on the speakers bureau and advisory boards for Teva, IMPAX, and ACADIA; is on the advisory board for U.S. World Meds; and is a consultant for Cynapsus and Pfizer.

SYNOPSIS: This observational study of 425 patients with a broad range of stages of Parkinson’s disease found that long-acting pramipexole and transdermal rotigotine were less likely to be associated with impulse control disorders than were immediate-release pramipexole and any formulation of ropinirole. This study highlights differences between dopamine agonists that may affect patient care.

SOURCE: Rizos A, Sauerbier A, Antonini A, et al. A European multicentre survey of impulse control behaviours in Parkinson’s disease patients treated with short- and long-acting dopamine agonists. Eur J Neurol 2016;23:1255-1261.

This observational study used retrospective and prospective data collection, with chart review and interviews, for patients with Parkinson’s disease (PD) to determine the occurrence of impulse control disorders (ICDs) in the context of dopamine agonist treatment. Specifically, the investigators focused on whether immediate-release formulations (pramipexole IR and ropinirole IR) would be associated with ICDs differently than long-acting formulations (pramipexole ER, ropinirole XL, rotigotine transdermal patch). Data were collected from charts of 425 PD patients who either were already taking or were starting dopamine agonist therapy, in eight European specialist centers over a three-year period of routine clinical care. Ascertainment of ICD was made by direct inquiry during clinic visits and, in part, by answers to specific questions on the non-motor rating scale. The cohort comprised 61% men, with mean age 68.3 (range 37-90) years, mean age of PD onset 61 (range 18-85) years, and mean disease duration 7.5 (range 0-37) years. Of the long-acting agonists, 43.1% of patients took rotigotine, 38.8% took ropinirole XL, and 17.9% took pramipexole ER. Of the short-acting agonists, 24.7% of patients took pramipexole IR and 10.1% took ropinirole XL. Overall, ICDs that were deemed clinically relevant were present in 13.4%, and this group of patients were slightly more likely to be men (79%) and have a younger age of onset (55.7 years). Interestingly, the percentages of ICDs varied quite markedly between agonists. In those using rotigotine, ICDs were only reported in 4.9%; in those using pramipexole, ICDs were reported in 6.6% for long-acting (ER) vs. 19% for short-acting (IR). However, for those using ropinirole, ICDs were similar for both formulations (13.9% and 14% for XL and IR, respectively). Only about half of these patients discontinued dopamine agonists, but how many reduced the dose is unclear. Curiously, of the ICDs reported (binge eating, gambling, hypersexuality, multiple), results suggest binge eating much more commonly in pramipexole IR than in ropinirole IR and XL, and hypersexuality more commonly with ropinirole (IR and XL).

COMMENTARY

The occurrence of ICDs associated with PD medications, and with dopamine agonists in particular, long has been a source of concern, with a seminal publication on pathological gambling in 11 subjects in 2005.1 Although ICDs initially were thought to be rare, in 2010, the DOMINION study of 3,090 PD patients in North America found that use of a dopamine agonist was associated with a 2- to 3.5-fold increase in risk of ICD, and that 17.1% of patients taking dopamine agonists suffered from at least one ICD. Given the potential and well-reported consequences of ICDs, this has contributed to a reluctance in some cases to use these drugs. Moreover, a “withdrawal syndrome” also has been described in some patients as agonists are stopped because of side effects, including ICDs. This creates difficulty in the clinic because despite established benefits, it is not easy to predict who is at risk of ICDs. Therefore, this study by Rizos and colleagues is a welcome step toward teasing out the complexity of dopamine agonist effects, and follows from another recent report that rotigotine is associated with a lower risk of ICDs than other agonists. However, the study leaves many questions unanswered. There is very little information on what happened to patients over time, although from the numbers reported, it seems many must have tried multiple agonists and also different doses at different times. This means the doses reported as taken are hard to interpret. Other medications, and their potential contributions, are represented as levodopa equivalents, but differences between groups are not discussed. A major drawback, as acknowledged by the investigators, is the lack of a formal screening tool (such as the Questionnaire for Impulsive-Compulsive Disorders, or QUIP) to detect ICDs in this study. However, one would imagine that any resulting underestimate of ICDs should apply across the board. Some of these investigators have suggested previously that long-acting formulations be considered as an alternative for those experiencing ICDs on short-acting agonists. Currently, there are too little data to have a high degree of confidence in that approach, and current advice remains to reduce and/or eliminate the dopamine agonist in cases of troublesome ICDs. However, if further studies support the notion that rotigotine and pramipexole ER are safer for patients from the point of view of ICDs, this will be cause for a change in practice.

REFERENCE

  1. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:1377-1381.