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Restless legs syndrome outside the blood–brain barrier – Exacerbation by domperidone in Parkinson's disease
Parkinsonism and Related Disorders 19 (2013) 92e94
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Restless legs syndrome outside the bloodebrain barrier e Exacerbation by domperidone in Parkinson’s disease S. Rios Romenets a, Y. Dauvilliers b, V. Cochen De Cock b, c, B. Carlander b, S. Bayard b, C. Galatas a, C. Wolfson c, R.B. Postuma a, * a b c
Department of Neurology, McGill University, Montreal General Hospital, 1650 Cedar Ave., Montreal L 7-312, Quebec H3G1A4, Canada Department of Neurology, Hôpital Gui de Chauliac, Montpellier, INSERM U1061, Montpellier, France Department of Epidemiology and Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 May 2012 Received in revised form 27 June 2012 Accepted 29 July 2012
Introduction: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the bloodebrain barrier, is commonly used in Parkinson’s disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson’s patients may have exacerbation of restless legs with domperidone. Methods: From two Parkinson’s disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications. Results: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p ¼ 0.010). Other medications were not associated with restless legs. Conclusion: This unexpected finding suggests that dopaminergic neurons outside of the bloodebrain barrier may be important in restless legs syndrome pathophysiology. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Restless legs syndrome Parkinson’s disease Domperidone
1. Introduction Despite considerable advances, our understanding of restless legs syndrome (RLS) pathophysiology remains incomplete. Many hypotheses including failure of bloodebrain iron transport [1], alterations in nigral iron deposition [1,2], and dysfunction of the dopaminergic hypothalamic A11-group [3e5] focus on central nervous system structures. On the other hand, preliminary functional analysis of genes implicated in RLS risk and possible links between peripheral neuropathy and RLS [6e8] suggest that peripheral structures may also be important. We encountered a striking case of idiopathic RLS that dramatically worsened with addition of domperidone to dopamine agonist therapy (see Supplemental Information). Domperidone is a peripherally-acting D2-receptor antagonist. Because it does not cross the bloodebrain barrier (BBB), it is often used to manage nausea and orthostatic hypotension in Parkinson’s disease (PD), without worsening extrapyramidal symptoms [9,10]. Based on
* Corresponding author. Tel.: þ1 514 934 8026; fax: þ1 514 934 8265. E-mail address: [email protected] (R.B. Postuma). 1353-8020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.07.019
current pathophysiologic models, this exacerbation was completely unanticipated. Therefore, we aimed to confirm the association by systematically assessing whether patients with PD taking domperidone had higher RLS frequency. 2. Methods Two cohorts of patients were selected, from the Movement Disorder Clinic at the McGill University Health Center [11], Montreal, and the Hôpital Gui de Chauliac, Montpellier. Both studies were approved by institutional Research Ethics Boards, and participants completed written informed consent. In both cohorts, diagnosis of RLS was made according to standard criteria [12]. Patients were excluded if they had dementia (Mini-Mental State Examination < 26 with functional impairment), or if, after the evaluation, an alternate cause of parkinsonism was diagnosed. In Montreal all participants were screened for RLS using the Non-Motor Symptom Questionnaire (NMS-Quest) [13], and a five-item questionnaire assessing International RLS Study Group diagnostic criteria [8]. Because many conditions can mimic RLS, patients who screened positive on either measure were interviewed by a movement disorders specialist to determine whether RLS was truly present. In Montreal, patients with RLS taking domperidone were queried (in an unblinded fashion) about timing of RLS onset vs. domperidone use (the start date of domperidone was not available in the Montpellier cohort). Those who had noticed exacerbation or initiation of RLS symptoms with domperidone were offered withdrawal, and changes in UPDRS and RLS severity (via the international RLS severity scale) were assessed in an open-label fashion. In Montpellier, a systematic interview assessing the 4 IRLS criteria was conducted directly by a sleep specialist. Domperidone use in Montpellier was
S. Rios Romenets et al. / Parkinsonism and Related Disorders 19 (2013) 92e94 assessed via review of the study database, and RLS diagnosis was assessed blinded to domperidone use. The primary outcome was the presence of RLS in patients taking vs. not taking domperidone. For the primary outcome, analysis was performed using logistic regression adjusting for age, sex, disease duration, UPDRS, levodopa dose, dopamine agonist, antidepressant, benzodiazepine, neuroleptic, gabapentin and Deep Brain Stimulation (DBS) use. Secondary outcomes were assessed using student t-tests for continuous variables, and Fisher’s exact tests for categorical variables.
3. Results One hundred eighty four patients participated; 75 from the Montreal cohort, and 109 from the Montpellier cohort. Average age was 66.8 8.4, 70% were men, and disease duration was 6.8 5.6 years. Of these, 27 were taking domperidone and 157 were not. There were no statistically significant differences between groups in age, sex, disease duration, dopamine agonist use, levodopa use, or UPDRS (Table 1). Overall, 13/46 (28%) of PD patients with RLS had onset of RLS before PD onset (2/13 (15%) patients with RLS taking domperidone and 11/33 (33%) not taking domperidone). One patient with RLS had a diagnosis of neuropathy (not taking domperidone). Patients taking domperidone were more likely to take antidepressants 12/27 (44%) vs. 22/157 (14%), but antidepressants were not associated with RLS (9/46 (20%) vs. 26/138 (19%), p ¼ 1.0). Twelve patients used DBS; DBS use was not associated with RLS (3/ 46 (7%) vs. 9/138 (7%), p ¼ 1.0). Four out of twenty seven patients taking domperidone received quetiapine vs. 0/157 in those without domperidone. There were no differences between use of benzodiazepines (including clonazepam) or gabapentin among patients taking vs. not taking domperidone. After the complete diagnostic interview, 13/27 (48%) patients on domperidone were confirmed as having RLS compared to 33/157 (21%) patients off domperidone. There were no significant differences in age, sex, disease duration, dopamine agonist use, antidepressant, benzodiazepine, neuroleptic, gabapentin, DBS use, level of serum ferritin or UPDRS between those with vs. without RLS. Levodopa dose was associated with RLS (714.2 462.9 vs. 565.8 409.7, p ¼ 0.011), but no other variables were associated. After adjustment for all these variables in logistic regression, the relationship between domperidone and RLS was statistically significant (p ¼ 0.003, adjusted OR ¼ 4.2). Upon removal of the 13 Table 1 Relationship between domperidone and disease variables in patients with Parkinson’s disease.
Age, y, mean SD Men:women (% men) Disease duration, y, mean SD UPDRS III, mean SD Total Levodopa dose, mg/d Dopamine agonist use, n (%) Antidepressant use, n (%) Benzodiazepine use, n (%) Neuroleptic use, n (%) Gabapentin use, n (%) DBS use, n (%) Serum ferritin, ng/mL Restless legs syndrome confirmed, n (%)
Taking domperidone (N ¼ 27)
Not taking domperidone (N ¼ 157)
p Value
66.7 7.1 17:10 (63%) 6.0 4.7
66.8 8.6 112:45 (71%) 7.1 5.8
0.44 0.37 0.93
28.6 10.8 598.5 379.6 12 (44%) 12 (44%) 8 (30%) 4 (15%) 1 (4%) 2 (7%) 127 85 (n ¼ 16) 13 (48%)
23.8 12.7 459.4 361.5 81 (52%) 22 (14%) 25 (16%) 0 (0%) 1 (1%) 10 (6%) 145 133 (n ¼ 85)
0.11 0.22 0.50 0.001 0.10 0.001 0.38 0.69 0.59
33 (21%)
0.003a
RLS ¼ restless legs syndrome; UPDRS ¼ Unified Parkinson Disease Rating Scale; DBS ¼ Deep Brain Stimulation; SD ¼ standard deviation; p values in bold are indicating statistical significance at a ¼ 0.05. a p value adjusted logistic regression, other p values are from unadjusted analyses (t-test, Fisher exact test).
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patients with RLS onset before PD, the odds ratio for domperidone increased from 4.2 to 5.1 (p ¼ 0.001, adjusted). The IRLSSG severity score was similar in RLS patients taking or not taking domperidone (16.8 7.6 vs. 19.0 5.4, n ¼ 40, p ¼ 0.37). The relationship between levodopa and RLS remained significant, after adjusting for all variables (p ¼ 0.011). Among patients with RLS, the mean IRLSSGSS was higher in patients taking higher levodopa dose (linear regression, p ¼ 0.017). No other medications were associated with RLS. In the Montreal cohort, 4/6 patients with RLS on domperidone noticed either new onset or exacerbation of symptoms coincident with starting domperidone (the remaining two had near-lifelong RLS). In the 2 patients who subsequently stopped domperidone, the IRLSSG dropped within days from 11 to 0, and from 23 to 12 respectively. To confirm that domperidone did not cross the bloodebrain barrier, we assessed the relationship between domperidone prescription and UPDRS change, via chart review, in 10 patients who started domperidone while under clinical follow-up. UPDRS before domperidone was 30.7 10.2 compared to 27.2 11.4 after. Therefore, consistent with its widespread use in PD, we found no evidence of exacerbation of parkinsonism with domperidone. 4. Discussion Our principal finding is that domperidone, a dopamine antagonist that does not cross the bloodebrain barrier, is associated with increased frequency of RLS in patients with PD. This finding has two main implications. The first is that we have found a novel side effect of domperidone; therefore, PD patients with inadequately controlled RLS who take domperidone may improve with domperidone withdrawal. The second implication is for RLS pathophysiology e if a peripheral dopaminergic antagonist can trigger RLS, dopaminergic neurons outside of the bloodebrain barrier may be important in RLS pathophysiology. Theories about the dopaminergic role of RLS focus mainly on two sites. Substantia nigra involvement is suggested by autopsy studies which find changes in dopaminergic neurons in the basal ganglia of patients in RLS, possibly related to cerebral iron insufficiency [2,14]. The other potential site is the dopaminergic A11 cell group, which originates in a small cluster of cells in the hypothalamus and synapses on spinal cord [3e5,15]. Of note, both areas are behind the bloodebrain/bloodespinal barrier; domperidone should have no direct influence on these regions. It is unclear which peripheral dopaminergic receptors could be involved in RLS pathogenesis; dopaminergic receptors exist in the lung, heart, kidney, blood vessels, adrenal gland, parathyroid gland and gastrointestinal tract [16e19], and may regulate blood pressure control and immune systems [17,20]. Another promising set of potential ‘peripheral’ dopaminergic targets are the circumventricular organs, brain areas that are not behind the bloodebrain barrier. Some of these areas have dopaminergic innervation; for example, tuberoinfundibular dopaminergic neurons regulate prolactin in the anterior hypothalamus [21], and subcallosal organ dopamine neurons may regulate blood pressure [22]. One very intriguing location is the pineal gland, a circumventricular organ which contains dopaminergic receptors and, via melatonin secretion, is involved in circadian rhythm generation [23,24]. In cell culture studies, D2-selective antagonists, such as domperidone, increase melatonin secretion [24]. In turn, melatonin may decrease dopamine secretionin the central nervous system [24], potentially exacerbating RLS (although this would presumably not occur in the substantia nigra, or parkinsonism would be exacerbated). Of note, a recent human study demonstrated that exogenous melatonin worsened RLS symptoms [25,26]. If domperidone increases
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melatonin secretion and melatonin inhibits central dopamine, a potential mechanism exists for our findings. In a secondary outcome analysis, we also found that levodopa dose may be associated with RLS independent of disease severity, and within patients with RLS, there was a positive correlation between levodopa dose and RLS severity. There is a controversial relationship between PD and RLS e many studies suggest higher prevalence of RLS in PD [27,28], but others do not [29]. One possible mechanism for an increased prevalence is augmentation; PD patients with ‘subclinical’ RLS are exposed to dopaminergic medications for years, and subsequent augmentation allows appearance of symptoms [30]. Augmentation occurs more with short-duration dopaminergic therapy (in particular levodopa), so our finding that levodopa use is associated with RLS independent of disease duration and motor severity is perhaps consistent with this notion. However, other groups have not noted a relationship between higher levodopa dose and RLS [27,29], so these results must be considered preliminary only. Some limitations of this study should be noted. RLS diagnosis is challenging in PD, with confounds like off-period pain, etc. To mitigate this, specialists with RLS expertise conducted prospective systematic interviews to ensure the diagnosis was truly present. Another limitation is that our study focused on PD patients, mainly because this is the population in whom domperidone is frequently chronically used. Of note, we and others have not noticed insufficient benefit of dopamine agonists in idiopathic RLS when domperidone was started simultaneously with the agonist e this could be simply due to simultaneous prescription of a highly-effective CNS agent with a weaker ‘peripheral’ exacerbator, or alternatively could suggest that domperidone works on augmentation mechanisms in PD. It would therefore be of considerable interest to assess RLS in other populations for whom domperidone is used. Third, the relationship between stopping domperidone and potential relief of RLS was open-label, and could be prone to placebo effect e these findings should be interpreted as suggestive only. Finally, although we adjusted for important potential confounds, an unrecognized confounder could always exist to explain our findings. In summary, domperidone, a dopamine antagonist that does not cross the bloodebrain barrier, appears to be able to trigger RLS in some cases of PD. In addition to having practical clinical implications, this finding may suggest novel mechanisms in RLS pathogenesis in the context of PD. Disclosure The authors report no conflicts of interest related to the study. Acknowledgment This study was supported by grants to RP from the Canadian Institutes of Health Research and by the Fonds de la recherche en santé du Québec. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2012.07.019. References [1] Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004 Jul;5(4):385e91.
[2] Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003 Aug 12;61(3):304e9. [3] Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010 Jun;6(6):337e46. [4] Ondo WG, He Y, Rajasekaran S, Le WD. Clinical correlates of 6hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000 Jan;15(1):154e8. [5] Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006 Jul 11; 67(1):125e30. [6] Gemignani F, Brindani F, Vitetta F, Marbini A, Calzetti S. Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy. J Peripher Nerv Syst 2007 Mar;12(1):50e3. [7] Polydefkis M, Allen RP, Hauer P, Earley CJ, Griffin JW, McArthur JC. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000 Oct 24;55(8):1115e21. [8] Hattan E, Chalk C, Postuma RB. Is there a higher risk of restless legs syndrome in peripheral neuropathy? Neurology 2009 Mar 17;72(11):955e60. [9] Barone JA. Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother 1999 Apr;33(4):429e40. [10] Ahmad N, Keith-Ferris J, Gooden E, Abell T. Making a case for domperidone in the treatment of gastrointestinal motility disorders. Curr Opin Pharmacol 2006 Dec;6(6):571e6. [11] Rios Romenets S, Wolfson C, Galatas C, Pelletier A, Altman R, Wadup L, et al. Validation of the non-motor symptoms questionnaire (NMS-Quest). Parkinsonism Relat Disord 2012 Jan;18(1):54e8. [12] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the national institutes of health. Sleep Med 2003 Mar;4(2):101e19. [13] Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, et al. International multicenter pilot study of the first comprehensive selfcompleted nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord 2006 Jul;21(7):916e23. [14] Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 2009 Sep;132(Pt 9):2403e12. [15] Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergictherapy-related augmentation in restless legs syndrome. Lancet Neurol 2006 Oct;5(10):878e86. [16] Lackovic Z, Neff NH. Minireview. Evidence that dopamine is a neurotransmitter in peripheral tissues. Life Sci 1983 Apr 11;32(15):1665e74. [17] Amenta F, Ricci A, Tayebati SK, Zaccheo D. The peripheral dopaminergic system: morphological analysis, functional and clinical applications. Ital J Anat Embryol 2002 Jul-Sep;107(3):145e67. [18] Bell C. Peripheral dopaminergic nerves. Pharmacol Ther 1989;44(2):157e79. [19] Amenta F, Ricci A, Rossodivita I, Avola R, Tayebati SK. The dopaminergic system in hypertension. Clin Exp Hypertens 2001 Jan-Feb;23(1e2):15e24. [20] Cheung PY, Barrington KJ. Renal dopamine receptors: mechanisms of action and developmental aspects. Cardiovasc Res 1996 Jan;31(1):2e6. [21] Ganong WF. Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 2000 MayJun;27(5e6):422e7. [22] Carmona-Calero EG-MI, Fernandez-Rodriguez P, Perez-Gonzalez H, GonzalezToledo J, Castaneyra-Ruiz L, Castaneyra-Ruiz A, et al. Dopamine betahydroxylase and p73 expression during aging and ventricular dilation in the cerebrospinal fluid and circumventricular organs of SHR rats. Cerebrospinal Fluid Res 2006:2. [23] Ebadi M, Govitrapong P. Neural pathways and neurotransmitters affecting melatonin synthesis. J Neural Transm Suppl 1986;21:125e55. [24] Santanavanich C, Chetsawang B, Ebadi M, Govitrapong P. Effects of D1- and D2-dopamine receptor activation on melatonin synthesis in bovine pinealocytes. J Pineal Res 2003 Oct;35(3):169e76. [25] Garcia-Borreguero D, Serrano C, Larrosa O, Granizo JJ. Circadian effects of dopaminergic treatment in restless legs syndrome. Sleep Med 2004 Jul;5(4): 413e20. [26] Whittom S, Dumont M, Petit D, Desautels A, Adam B, Lavigne G, et al. Effects of melatonin and bright light administration on motor and sensory symptoms of RLS. Sleep Med 2010 Apr;11(4):351e5. [27] Peralta CM, Frauscher B, Seppi K, Wolf E, Wenning GK, Hogl B, et al. Restless legs syndrome in Parkinson’s disease. Mov Disord 2009 Oct 30;24(14):2076e80. [28] Gomez-Esteban JC, Zarranz JJ, Tijero B, Velasco F, Barcena J, Rouco I, et al. Restless legs syndrome in Parkinson’s disease. Mov Disord 2007 Oct 15; 22(13):1912e6. [29] Verbaan D, van Rooden SM, van Hilten JJ, Rijsman RM. Prevalence and clinical profile of restless legs syndrome in Parkinson’s disease. Mov Disord 2010 Oct 15;25(13):2142e7. [30] Moller JC, Unger M, Stiasny-Kolster K, Oertel WH. Restless legs syndrome (RLS) and Parkinson’s disease (PD)-related disorders or different entities? J Neurol Sci 2010 Feb 15;289(1e2):135e7.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Restless legs syndrome outside the bloodebrain barrier e Exacerbation by domperidone in Parkinson’s disease S. Rios Romenets a, Y. Dauvilliers b, V. Cochen De Cock b, c, B. Carlander b, S. Bayard b, C. Galatas a, C. Wolfson c, R.B. Postuma a, * a b c
Department of Neurology, McGill University, Montreal General Hospital, 1650 Cedar Ave., Montreal L 7-312, Quebec H3G1A4, Canada Department of Neurology, Hôpital Gui de Chauliac, Montpellier, INSERM U1061, Montpellier, France Department of Epidemiology and Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 May 2012 Received in revised form 27 June 2012 Accepted 29 July 2012
Introduction: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the bloodebrain barrier, is commonly used in Parkinson’s disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson’s patients may have exacerbation of restless legs with domperidone. Methods: From two Parkinson’s disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications. Results: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p ¼ 0.010). Other medications were not associated with restless legs. Conclusion: This unexpected finding suggests that dopaminergic neurons outside of the bloodebrain barrier may be important in restless legs syndrome pathophysiology. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Restless legs syndrome Parkinson’s disease Domperidone
1. Introduction Despite considerable advances, our understanding of restless legs syndrome (RLS) pathophysiology remains incomplete. Many hypotheses including failure of bloodebrain iron transport [1], alterations in nigral iron deposition [1,2], and dysfunction of the dopaminergic hypothalamic A11-group [3e5] focus on central nervous system structures. On the other hand, preliminary functional analysis of genes implicated in RLS risk and possible links between peripheral neuropathy and RLS [6e8] suggest that peripheral structures may also be important. We encountered a striking case of idiopathic RLS that dramatically worsened with addition of domperidone to dopamine agonist therapy (see Supplemental Information). Domperidone is a peripherally-acting D2-receptor antagonist. Because it does not cross the bloodebrain barrier (BBB), it is often used to manage nausea and orthostatic hypotension in Parkinson’s disease (PD), without worsening extrapyramidal symptoms [9,10]. Based on
* Corresponding author. Tel.: þ1 514 934 8026; fax: þ1 514 934 8265. E-mail address: [email protected] (R.B. Postuma). 1353-8020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.07.019
current pathophysiologic models, this exacerbation was completely unanticipated. Therefore, we aimed to confirm the association by systematically assessing whether patients with PD taking domperidone had higher RLS frequency. 2. Methods Two cohorts of patients were selected, from the Movement Disorder Clinic at the McGill University Health Center [11], Montreal, and the Hôpital Gui de Chauliac, Montpellier. Both studies were approved by institutional Research Ethics Boards, and participants completed written informed consent. In both cohorts, diagnosis of RLS was made according to standard criteria [12]. Patients were excluded if they had dementia (Mini-Mental State Examination < 26 with functional impairment), or if, after the evaluation, an alternate cause of parkinsonism was diagnosed. In Montreal all participants were screened for RLS using the Non-Motor Symptom Questionnaire (NMS-Quest) [13], and a five-item questionnaire assessing International RLS Study Group diagnostic criteria [8]. Because many conditions can mimic RLS, patients who screened positive on either measure were interviewed by a movement disorders specialist to determine whether RLS was truly present. In Montreal, patients with RLS taking domperidone were queried (in an unblinded fashion) about timing of RLS onset vs. domperidone use (the start date of domperidone was not available in the Montpellier cohort). Those who had noticed exacerbation or initiation of RLS symptoms with domperidone were offered withdrawal, and changes in UPDRS and RLS severity (via the international RLS severity scale) were assessed in an open-label fashion. In Montpellier, a systematic interview assessing the 4 IRLS criteria was conducted directly by a sleep specialist. Domperidone use in Montpellier was
S. Rios Romenets et al. / Parkinsonism and Related Disorders 19 (2013) 92e94 assessed via review of the study database, and RLS diagnosis was assessed blinded to domperidone use. The primary outcome was the presence of RLS in patients taking vs. not taking domperidone. For the primary outcome, analysis was performed using logistic regression adjusting for age, sex, disease duration, UPDRS, levodopa dose, dopamine agonist, antidepressant, benzodiazepine, neuroleptic, gabapentin and Deep Brain Stimulation (DBS) use. Secondary outcomes were assessed using student t-tests for continuous variables, and Fisher’s exact tests for categorical variables.
3. Results One hundred eighty four patients participated; 75 from the Montreal cohort, and 109 from the Montpellier cohort. Average age was 66.8 8.4, 70% were men, and disease duration was 6.8 5.6 years. Of these, 27 were taking domperidone and 157 were not. There were no statistically significant differences between groups in age, sex, disease duration, dopamine agonist use, levodopa use, or UPDRS (Table 1). Overall, 13/46 (28%) of PD patients with RLS had onset of RLS before PD onset (2/13 (15%) patients with RLS taking domperidone and 11/33 (33%) not taking domperidone). One patient with RLS had a diagnosis of neuropathy (not taking domperidone). Patients taking domperidone were more likely to take antidepressants 12/27 (44%) vs. 22/157 (14%), but antidepressants were not associated with RLS (9/46 (20%) vs. 26/138 (19%), p ¼ 1.0). Twelve patients used DBS; DBS use was not associated with RLS (3/ 46 (7%) vs. 9/138 (7%), p ¼ 1.0). Four out of twenty seven patients taking domperidone received quetiapine vs. 0/157 in those without domperidone. There were no differences between use of benzodiazepines (including clonazepam) or gabapentin among patients taking vs. not taking domperidone. After the complete diagnostic interview, 13/27 (48%) patients on domperidone were confirmed as having RLS compared to 33/157 (21%) patients off domperidone. There were no significant differences in age, sex, disease duration, dopamine agonist use, antidepressant, benzodiazepine, neuroleptic, gabapentin, DBS use, level of serum ferritin or UPDRS between those with vs. without RLS. Levodopa dose was associated with RLS (714.2 462.9 vs. 565.8 409.7, p ¼ 0.011), but no other variables were associated. After adjustment for all these variables in logistic regression, the relationship between domperidone and RLS was statistically significant (p ¼ 0.003, adjusted OR ¼ 4.2). Upon removal of the 13 Table 1 Relationship between domperidone and disease variables in patients with Parkinson’s disease.
Age, y, mean SD Men:women (% men) Disease duration, y, mean SD UPDRS III, mean SD Total Levodopa dose, mg/d Dopamine agonist use, n (%) Antidepressant use, n (%) Benzodiazepine use, n (%) Neuroleptic use, n (%) Gabapentin use, n (%) DBS use, n (%) Serum ferritin, ng/mL Restless legs syndrome confirmed, n (%)
Taking domperidone (N ¼ 27)
Not taking domperidone (N ¼ 157)
p Value
66.7 7.1 17:10 (63%) 6.0 4.7
66.8 8.6 112:45 (71%) 7.1 5.8
0.44 0.37 0.93
28.6 10.8 598.5 379.6 12 (44%) 12 (44%) 8 (30%) 4 (15%) 1 (4%) 2 (7%) 127 85 (n ¼ 16) 13 (48%)
23.8 12.7 459.4 361.5 81 (52%) 22 (14%) 25 (16%) 0 (0%) 1 (1%) 10 (6%) 145 133 (n ¼ 85)
0.11 0.22 0.50 0.001 0.10 0.001 0.38 0.69 0.59
33 (21%)
0.003a
RLS ¼ restless legs syndrome; UPDRS ¼ Unified Parkinson Disease Rating Scale; DBS ¼ Deep Brain Stimulation; SD ¼ standard deviation; p values in bold are indicating statistical significance at a ¼ 0.05. a p value adjusted logistic regression, other p values are from unadjusted analyses (t-test, Fisher exact test).
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patients with RLS onset before PD, the odds ratio for domperidone increased from 4.2 to 5.1 (p ¼ 0.001, adjusted). The IRLSSG severity score was similar in RLS patients taking or not taking domperidone (16.8 7.6 vs. 19.0 5.4, n ¼ 40, p ¼ 0.37). The relationship between levodopa and RLS remained significant, after adjusting for all variables (p ¼ 0.011). Among patients with RLS, the mean IRLSSGSS was higher in patients taking higher levodopa dose (linear regression, p ¼ 0.017). No other medications were associated with RLS. In the Montreal cohort, 4/6 patients with RLS on domperidone noticed either new onset or exacerbation of symptoms coincident with starting domperidone (the remaining two had near-lifelong RLS). In the 2 patients who subsequently stopped domperidone, the IRLSSG dropped within days from 11 to 0, and from 23 to 12 respectively. To confirm that domperidone did not cross the bloodebrain barrier, we assessed the relationship between domperidone prescription and UPDRS change, via chart review, in 10 patients who started domperidone while under clinical follow-up. UPDRS before domperidone was 30.7 10.2 compared to 27.2 11.4 after. Therefore, consistent with its widespread use in PD, we found no evidence of exacerbation of parkinsonism with domperidone. 4. Discussion Our principal finding is that domperidone, a dopamine antagonist that does not cross the bloodebrain barrier, is associated with increased frequency of RLS in patients with PD. This finding has two main implications. The first is that we have found a novel side effect of domperidone; therefore, PD patients with inadequately controlled RLS who take domperidone may improve with domperidone withdrawal. The second implication is for RLS pathophysiology e if a peripheral dopaminergic antagonist can trigger RLS, dopaminergic neurons outside of the bloodebrain barrier may be important in RLS pathophysiology. Theories about the dopaminergic role of RLS focus mainly on two sites. Substantia nigra involvement is suggested by autopsy studies which find changes in dopaminergic neurons in the basal ganglia of patients in RLS, possibly related to cerebral iron insufficiency [2,14]. The other potential site is the dopaminergic A11 cell group, which originates in a small cluster of cells in the hypothalamus and synapses on spinal cord [3e5,15]. Of note, both areas are behind the bloodebrain/bloodespinal barrier; domperidone should have no direct influence on these regions. It is unclear which peripheral dopaminergic receptors could be involved in RLS pathogenesis; dopaminergic receptors exist in the lung, heart, kidney, blood vessels, adrenal gland, parathyroid gland and gastrointestinal tract [16e19], and may regulate blood pressure control and immune systems [17,20]. Another promising set of potential ‘peripheral’ dopaminergic targets are the circumventricular organs, brain areas that are not behind the bloodebrain barrier. Some of these areas have dopaminergic innervation; for example, tuberoinfundibular dopaminergic neurons regulate prolactin in the anterior hypothalamus [21], and subcallosal organ dopamine neurons may regulate blood pressure [22]. One very intriguing location is the pineal gland, a circumventricular organ which contains dopaminergic receptors and, via melatonin secretion, is involved in circadian rhythm generation [23,24]. In cell culture studies, D2-selective antagonists, such as domperidone, increase melatonin secretion [24]. In turn, melatonin may decrease dopamine secretionin the central nervous system [24], potentially exacerbating RLS (although this would presumably not occur in the substantia nigra, or parkinsonism would be exacerbated). Of note, a recent human study demonstrated that exogenous melatonin worsened RLS symptoms [25,26]. If domperidone increases
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melatonin secretion and melatonin inhibits central dopamine, a potential mechanism exists for our findings. In a secondary outcome analysis, we also found that levodopa dose may be associated with RLS independent of disease severity, and within patients with RLS, there was a positive correlation between levodopa dose and RLS severity. There is a controversial relationship between PD and RLS e many studies suggest higher prevalence of RLS in PD [27,28], but others do not [29]. One possible mechanism for an increased prevalence is augmentation; PD patients with ‘subclinical’ RLS are exposed to dopaminergic medications for years, and subsequent augmentation allows appearance of symptoms [30]. Augmentation occurs more with short-duration dopaminergic therapy (in particular levodopa), so our finding that levodopa use is associated with RLS independent of disease duration and motor severity is perhaps consistent with this notion. However, other groups have not noted a relationship between higher levodopa dose and RLS [27,29], so these results must be considered preliminary only. Some limitations of this study should be noted. RLS diagnosis is challenging in PD, with confounds like off-period pain, etc. To mitigate this, specialists with RLS expertise conducted prospective systematic interviews to ensure the diagnosis was truly present. Another limitation is that our study focused on PD patients, mainly because this is the population in whom domperidone is frequently chronically used. Of note, we and others have not noticed insufficient benefit of dopamine agonists in idiopathic RLS when domperidone was started simultaneously with the agonist e this could be simply due to simultaneous prescription of a highly-effective CNS agent with a weaker ‘peripheral’ exacerbator, or alternatively could suggest that domperidone works on augmentation mechanisms in PD. It would therefore be of considerable interest to assess RLS in other populations for whom domperidone is used. Third, the relationship between stopping domperidone and potential relief of RLS was open-label, and could be prone to placebo effect e these findings should be interpreted as suggestive only. Finally, although we adjusted for important potential confounds, an unrecognized confounder could always exist to explain our findings. In summary, domperidone, a dopamine antagonist that does not cross the bloodebrain barrier, appears to be able to trigger RLS in some cases of PD. In addition to having practical clinical implications, this finding may suggest novel mechanisms in RLS pathogenesis in the context of PD. Disclosure The authors report no conflicts of interest related to the study. Acknowledgment This study was supported by grants to RP from the Canadian Institutes of Health Research and by the Fonds de la recherche en santé du Québec. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2012.07.019. References [1] Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004 Jul;5(4):385e91.
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