Reducing the dosage of dopamine agonists may lead to profound disability among some patients with Parkinson’s disease, according to a study in the January Archives of Neurology.
Patients who experience dopamine agonist withdrawal syndrome (DAWS) have symptoms that are similar to those accompanying withdrawal from other psychostimulant drugs such as cocaine. These symptoms include anxiety, panic attacks, agoraphobia, depression, dysphoria, fatigue, pain, and drug cravings, and are not alleviated by levodopa or other Parkinson’s disease medications, reported Christina A. Rabinak, BSE, and Melissa J. Nirenberg, MD, PhD, of the Department of Neurology and Neuroscience, Weill Cornell Medical College, in New York City.
All patients who experienced DAWS had baseline impulse control disorders. A premorbid history of anxiety was present in four of these participants, two had had depression, three had had prior smoking, and two had used marijuana. Patients with DAWS had higher baseline dopamine agonist doses and greater cumulative dopamine agonist exposure. Patients with DAWS also had “considerably lower” Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores than those without, even though they had a comparable disease duration and similar total dopaminergic medication use; the researchers, therefore, speculate that patients susceptible to DAWS may have a relatively benign motor phenotype.
“The clinical manifestations of DAWS were highly stereotyped and closely resembled other psychostimulant withdrawal syndromes, with prominent psychiatric (anxiety, panic attacks, dysphoria, depression, agitation, irritability, fatigue) and autonomic (orthostatic hypertension, diaphoresis) manifestations,” stated the researchers. “Levodopa, other Parkinson’s disease medications, antidepressants, anxiolytics, and psychotherapy were of no benefit in mitigating DAWS symptoms.” Because of the severity of their DAWS symptoms, three subjects were never able to discontinue the dopamine agonist and experienced impulse control disorders.
Based on these findings, the authors recommend “close monitoring of patients—particularly those with impulse control disorders—whenever dopamine agonists are withdrawn.” In addition, they recommend that physicians “strongly consider tapering dopamine agonists as soon as impulse control disorders develop, because high cumulative dopamine agonist exposure appears to increase the risk and severity of DAWS and decrease the chance of successful discontinuation of the dopamine agonist and resolution of impulse control disorders.”
“DAWS was usually misinterpreted as undermedication or end-of-dose wearing off but in all cases proved to be refractory to levodopa, persisting even when patients were in the on state and/or markedly overmedicated,” the researchers stated. “Less commonly, the symptoms were interpreted as a primary psychiatric disorder. In all cases, the symptoms temporally correlated with dopamine agonist withdrawal and rapidly and selectively remitted with dopamine agonist replacement, consistent with a drug-specific withdrawal syndrome.”
The investigators conducted their retrospective cohort study in 93 nondemented patients with Parkinson’s disease. Systematic record reviews were used to identify all cases of DAWS, defined as a “severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other Parkinson’s disease medications, and cannot be accounted for by other clinical factors.” Participants with DAWS were compared with those in the cohort who underwent uneventful dopamine agonist withdrawal.
Forty patients (43%) were treated with a dopamine agonist, and 26 (28%) had their dopamine agonist tapered during routine patient care. The presence of an impulse control disorder (such as compulsive eating, compulsive buying, pathologic gambling, and hypersexuality), a known side-effect of dopamine agonists, was the most common reason for tapering their dosage, occurring in 15 subjects (38% of those treated with a dopamine agonist and 58% of those who had their dopamine agonist tapered). Hyperinsomnia, psychosis, confusion, cognitive impairment, dizziness, orthostatic hypotension, and peripheral edema were other reasons given for reducing drug dosage. Thirteen participants had their dopamine agonist discontinued, and 13 had the dosage reduced, all with compensatory increases in levodopa dosage, according to the researchers.
Among the 26 subjects who had their drug tapered, five (19%) developed DAWS, with stereotyped symptoms that included anxiety, panic attacks, depression, dysphoria, agitation, insomnia, generalized pain, and drug cravings, among others. “In all cases, the onset of these symptoms correlated with initiation of the dopamine agonist taper, and the severity of symptoms increased with incremental dose reductions,” reported the study authors.
—Colby Stong