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Comment z Dopamine agonist withdrawal syndrome Managing dopamine agonist withdrawal syndrome in Parkinson’s disease Andrea J Lindahl MA, MD, FRCP, Douglas G MacMahon FRCP Dopamine agonist withdrawal syndrome (DAWS) has recently been named in the Archives of Neurology. It describes a cluster of symptoms occurring in Parkinson’s disease patients with impulse control disorders on tapering down or withdrawal of their dopamine agonist. Drs Lindahl and MacMahon discuss the risk factors for the development of DAWS and some approaches to its management. D opamine agonists have become widely used in the management of Parkinson’s disease (PD) with considerable benefits for many patients. However, as their use has extended, hitherto unrecognised problems have emerged – most recently impulse control disorders (ICDs)1,2 and, as a consequence of the need to down-titrate or withdraw the agonist, the recently named dopamine agonist withdrawal syndrome (DAWS).3 Anecdotal experiences of the adverse effects of sudden withdrawal of dopaminergic therapies have been recognised for many years – especially the physical manifestations of the neuroleptic malignant syndrome – and yet one still hears horrific stories of wellintentioned, yet potentially disastrous, effects of agonist withdrawal. The case report described by Cunnington et al. in this issue (see p. 24) is included to stimulate discussion, particularly among nonspecialists in movement disorders who may not be familiar with these syndromes. A recent posting on the National Parkinson Foundation website shows this still to be a very real and live issue,4 and Parkinson’s UK has recently established a Steering Group to address the issue. The prominence of ICDs has led to increased recognition of the prevalence of DAWS, and an urgent need for it to be managed better. 4 While dopaminergic medication, particularly dopamine agonists, may induce ICDs in a minority of patients, the majority are somehow protected from this adverse effect. Antonini’s group reported a prevalence of ICDs of 28 per cent in an Italian cohort (and 20 per cent in controls). 5 Curiously, they also found in another study that 17.5 per cent of drug-naïve PD patients screened positive for at least one ICD, although none had a disorder based on DSM-IV criteria, and so were presumed to have less severe illness.6 These frequencies were similar to healthy controls. Nevertheless, male patients with early-onset PD appear to be more susceptible to ICDs, and other predisposing factors – including personality traits, prior dependency on drugs or alcohol and any family history of alcohol or drug abuse – are contentious, but should suggest caution. The possible identification of genetic predisposition requires a genome-wide search, with interesting analogies to dopaminergic receptor genotypes predisposing to gambling tendencies. Functional imaging may also provide an important tool to study this phenomenon in vivo.7 Management approaches In terms of management, most authors favour a gradual (rather Progress in Neurology and Psychiatry than sudden) withdrawal of dopamine agonist, as tolerated, with additional therapies to address the dopaminergic deficit. Other approaches have included the off-licence use of apomorphine 8 and several case reports have been published suggesting a possible role for subthalamic stimulation9,10 (although this has also been reported as a cause of ICDs11 and DAWS12); enteral carbidopa/ levodopa infusions; 13 carbama zepine;14 amantadine15 (although this drug has also been incriminated in the genesis of the syndrome); zonisamide;16 or clozapine.17 We have anecdotal experience (unpublished) of the use of rotigotine patches, although these too have also been rarely cited as yet another cause of ICDs.18 The case of DAWS described in this issue demonstrates the need for careful monitoring of patients, and the importance of patient and carer/mentor education. It is important to warn (and carefully annotate for medicolegal reasons) patients and their close family before starting these drugs, and at regular intervals thereafter, of the importance of seeking help should ICDs become apparent, and also advocate caution during any drug titration or surgery. Potentially, the QUIP questionnaire (or a shorter simplified version thereof) may be helpful in www.progressnp.com Dopamine agonist withdrawal syndrome clinical practice.19 Non-specialists need to be aware of the consequences of ill-advised dosage adjustment, and especially to exercise caution in the management of nil by mouth situations when transdermal or enteral medication should be carefully considered. Perhaps one could suggest that this is a suitable topic to be aired at journal clubs, grand rounds and other postgraduate events in order to increase awareness among colleagues and improve patient care from both hospitals’ and patients’ perspectives. There is a wealth of up to date information and resources on ICDs for healthcare professionals and patients on the Parkinson’s UK website www.parkinsons.org.uk or by calling its helpline on 0808 800 0303. Declaration of interests Dr MacMahon is a Trustee of Parkinson’s UK. Dr Lindahl is a Consultant Neurologist and Dr MacMahon is a Consultant Physician at University Hospitals, Coventry and Warwickshire NHS Trust, Coventry References 1. Driver-Dunkley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61:422-3. 2. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson’s disease. Arch Neurol 2010;67(5):589-95. 3. Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson’s disease. Arch Neurol 2010;67(1):58-63. 4. http://forum.parkinson.org/index.php?/ topic/10922-going-through-daws-when-getting-off-mirapex-due-to-icd/ accessed 23.5.11. 5. Isaias IU, Siri C, Cilia R, et al. The relationship between impulsivity and impulse control disorders in Parkinson’s disease. Movement Disord 2008;23(3):411-5. 6. Antonini A, Siri C, Santangelo G, et al . Impulsivity and compulsivity in drug-naïve patients with Parkinson's disease. Movement Disord 2011;26(3):464-8. doi: 10.1002/ mds.23501. Epub Feb 10, 2011. 7. Cilia R, van Eimeren T. Impulse control disorders in Parkinson’s disease: seeking a roadmap toward a better understanding. Brain Struct Funct 2011; May 4. [Epub ahead of print] 8. Schlesinger I, Erikh I, Zaaroor M. Dopamine agonist withdrawal syndrome: the apomorphine solution. Arch Neurol 2010; 67(9):1155, author reply 1156. 9. Bandini F, Primavera A, Pizzorno M, Cocito L. Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson’s disease. Parkinsonism Relat Disord 2007;13:369-71. z Comment 10. Halbig TD, Tse W, Frisina PG, et al . Subthalamic deep brain stimulation and impulse control in Parkinson’s disease. Eur J Neurol 2009;16:493-7. 11. Demetriades P, Rickards H, Cavanna AE. Impulse control disorders following deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: clinical aspects. Parkinsons Dis 2011;2011:658415. 12. Nirenberg MJ. Dopamine agonist withdrawal syndrome and non-motor symptoms after Parkinson’s disease surgery. Brain 2010;133(11): e155, author reply 156. Epub 2010, Jul 21. 13. Gerschlager W, Bloem BR. Managing pathological gambling in Parkinson’s disease with enteral levodopa/carbidopa infusions. Movement Disord 2009;24:1858-60. 14. Bach JP, Oertel WH, Dodel R, Jessen F. Treatment of hypersexuality in Parkinson’s disease with carbamazepine – a case report. Movement Disord 2009;24:1241-42. 15. Thomas A, Bonanni L, Gambi F, et al. Pathological gambling in Parkinson disease is reduced by amantadine. Ann Neurol 2010;68:400-4. 16. Bermejo PE, Ruiz-Huete C, Anciones B. Zonisamide in managing impulse control disorders in Parkinson’s disease. J Neurol 2010;257:1682-5. 17. Rotondo A, Bosco D, Plastino M, et al . Clozapine for medication-related pathological gambling in Parkinson disease. Movement Disord 2010;25:1994-5. 18. Wingo TS, Evatt M, Scott B, et al. Impulse control disorders arising in 3 patients treated with rotigotine. Clin Neuropharmacol 2009; 32(2):59-62. 19. Weintraub D, Hoops S, Shea JA, et al . Validation of the questionnaire for impulsivecompulsive disorders in Parkinson's disease. Movement Disord 2009;24(10):1461-7. [QUIP questionnaire] Visit us online Progress in Neurology and Psychiatry’s dedicated website www.progressnp.com has been redesigned and now features news, events diary, links to continuing professional development resources and journal supplements. More new features will be appearing over the coming months. com – www.progressnp.com – www.progressnp.com – www.progressnp.com – www