Clinical Features of Dopamine Agonist Withdrawal Syndrome
Background Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS).
Objectives The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic.
Methods We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable.
Results Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS−). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS− patients (p<0.0001). DAWS+ and DAWS− patients did not differ in other variables.
Conclusion DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.
Dopamine is a critical neurotransmitter in mesocorticolimbic circuits involved in reward. Drugs that stimulate this circuit, such as amphetamines and cocaine, are a major societal cause of addiction. Dopamine replacement therapies (DRT) replenish the nigrostriatal pathway to control the motor symptoms of Parkinson's disease (PD), but also stimulate mesocorticolimbic circuits that are relatively intact, resulting in several addiction-related syndromes.
Among substance addiction syndromes reported in patients with PD on DRT, the dopamine dysregulation syndrome (DDS) is characterised by compulsive drug consumption accompanied by psychomotor agitation and euphoria, drug-related dyskinesias, resistance to dose reduction and withdrawal symptoms characterised by depression, anxiety and impairment in occupational and social functioning.
Impulse control disorders (ICD), commonly involving pathological gambling, hypersexuality, compulsive buying and compulsive eating, constitute a second type of DRT-related disinhibitory psychopathology considered a behavioural addition. ICD appear much more commonly in patients treated with dopamine agonists (DA), in whom they are reported in 14–17% of cases, while in patients with levodopa treatment the frequency ranges from 0.7% to 7%.
The clinical manifestations of dopamine agonist withdrawal syndrome (DAWS) resemble other psychostimulant withdrawal syndromes and the observed lack of response to levodopa, antidepressants and anxiolytics and the improvement with DA replacement are consistent with a drug-specific withdrawal syndrome. Rabinak and Nirenberg postulated that the patients with DAWS belong to a 'mesocorticolimbic variant' of PD, with disproportionate mesocorticolimbic versus nigrostriatal dopaminergic dysfunction, increased vulnerability to DAWS and ICD.
Most patients with ICD do not use DRT in a compulsive manner. On the other hand, the dose escalation in DDS patients can be accompanied by the development of ICD. Okai et al reviewed the problems of diagnosing and assessing the severity of ICD and proposed an extension to the criteria for DDS diagnosis.
The apathy that develops in PD patients following subthalamic nucleus stimulation has been linked to the drastic reduction in medication after surgery, and can be considered a DRT-related withdrawal syndrome. In contrast to this restricted postsurgical withdrawal syndrome, in a cohort of PD patients enrolled in a structured longitudinal study, Rabinak and Nirenberg reported symptoms similar to addictive drug withdrawal developing on withdrawal or attempted withdrawal of DA. They defined the DAWS as a severe stereotyped cluster of physical and psychological symptoms that correlate with DA withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other PD medications, and cannot be attributed to other clinical factors. DAWS comprises psychiatric symptoms such as anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain, and drug cravings and autonomic signs and symptoms such as orthostatic hypotension, dizziness, nausea and diaphoresis.
We aimed to determine the frequency of DAWS, the determinants for developing this syndrome, and the outcome of DAWS in a population of PD patients followed in a movement disorders clinic.
Abstract and Introduction
Abstract
Background Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS).
Objectives The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic.
Methods We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable.
Results Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS−). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS− patients (p<0.0001). DAWS+ and DAWS− patients did not differ in other variables.
Conclusion DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.
Introduction
Dopamine is a critical neurotransmitter in mesocorticolimbic circuits involved in reward. Drugs that stimulate this circuit, such as amphetamines and cocaine, are a major societal cause of addiction. Dopamine replacement therapies (DRT) replenish the nigrostriatal pathway to control the motor symptoms of Parkinson's disease (PD), but also stimulate mesocorticolimbic circuits that are relatively intact, resulting in several addiction-related syndromes.
Among substance addiction syndromes reported in patients with PD on DRT, the dopamine dysregulation syndrome (DDS) is characterised by compulsive drug consumption accompanied by psychomotor agitation and euphoria, drug-related dyskinesias, resistance to dose reduction and withdrawal symptoms characterised by depression, anxiety and impairment in occupational and social functioning.
Impulse control disorders (ICD), commonly involving pathological gambling, hypersexuality, compulsive buying and compulsive eating, constitute a second type of DRT-related disinhibitory psychopathology considered a behavioural addition. ICD appear much more commonly in patients treated with dopamine agonists (DA), in whom they are reported in 14–17% of cases, while in patients with levodopa treatment the frequency ranges from 0.7% to 7%.
The clinical manifestations of dopamine agonist withdrawal syndrome (DAWS) resemble other psychostimulant withdrawal syndromes and the observed lack of response to levodopa, antidepressants and anxiolytics and the improvement with DA replacement are consistent with a drug-specific withdrawal syndrome. Rabinak and Nirenberg postulated that the patients with DAWS belong to a 'mesocorticolimbic variant' of PD, with disproportionate mesocorticolimbic versus nigrostriatal dopaminergic dysfunction, increased vulnerability to DAWS and ICD.
Most patients with ICD do not use DRT in a compulsive manner. On the other hand, the dose escalation in DDS patients can be accompanied by the development of ICD. Okai et al reviewed the problems of diagnosing and assessing the severity of ICD and proposed an extension to the criteria for DDS diagnosis.
The apathy that develops in PD patients following subthalamic nucleus stimulation has been linked to the drastic reduction in medication after surgery, and can be considered a DRT-related withdrawal syndrome. In contrast to this restricted postsurgical withdrawal syndrome, in a cohort of PD patients enrolled in a structured longitudinal study, Rabinak and Nirenberg reported symptoms similar to addictive drug withdrawal developing on withdrawal or attempted withdrawal of DA. They defined the DAWS as a severe stereotyped cluster of physical and psychological symptoms that correlate with DA withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other PD medications, and cannot be attributed to other clinical factors. DAWS comprises psychiatric symptoms such as anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain, and drug cravings and autonomic signs and symptoms such as orthostatic hypotension, dizziness, nausea and diaphoresis.
We aimed to determine the frequency of DAWS, the determinants for developing this syndrome, and the outcome of DAWS in a population of PD patients followed in a movement disorders clinic.