<?xml version="1.0" encoding="UTF-8" standalone="yes"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.2d1 20170631//EN" "JATS-journalpublishing1.dtd">
<article xlink="http://www.w3.org/1999/xlink" dtd-version="1.0"><Article><Journal><PublisherName>jneuro</PublisherName><JournalTitle>Journal of Neurology and Neuropsychiatry</JournalTitle><PISSN>c</PISSN><EISSN>o</EISSN><Volume-Issue>Volume 2 Issue 1 (Jan-June)</Volume-Issue><IssueTopic>Multidisciplinary</IssueTopic><IssueLanguage>English</IssueLanguage><Season>6 months</Season><SpecialIssue>N</SpecialIssue><SupplementaryIssue>N</SupplementaryIssue><IssueOA>Y</IssueOA><PubDate><Year>2025</Year><Month>07</Month><Day>30</Day></PubDate><ArticleType>Neurological Disorder</ArticleType><ArticleTitle>Subcutaneous Apomorphine Infusion Effects on OFF Time and Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis</ArticleTitle><SubTitle/><ArticleLanguage>English</ArticleLanguage><ArticleOA>Y</ArticleOA><FirstPage>3</FirstPage><LastPage>16</LastPage><AuthorList><Author><FirstName>Paula Abola</FirstName><LastName>1</LastName><AuthorLanguage>English</AuthorLanguage><Affiliation/><CorrespondingAuthor>N</CorrespondingAuthor><ORCID/><FirstName>*</FirstName><AuthorLanguage>English</AuthorLanguage><Affiliation/><CorrespondingAuthor>Y</CorrespondingAuthor><ORCID/><FirstName>Benjamin Wolden 1 and Mitchell</FirstName><LastName>Wolden1</LastName><AuthorLanguage>English</AuthorLanguage><Affiliation/><CorrespondingAuthor>Y</CorrespondingAuthor><ORCID/></Author></AuthorList><DOI>10.71117/JNNP.2025.2102</DOI><Abstract>Background: Parkinson’s Disease (PD) is a progressive neurodegenerative disorder characterized by motor fluctuations and dyskinesias that become increasingly challenging to manage in advanced stages. Continuous subcutaneous Apomorphine infusion offers a less invasive alternative to device-aided therapies such as deep brain stimulation and Levodopa-Carbidopa intestinal gel. This systematic review and meta-analysis aimed to evaluate the efficacy of Apomorphine infusion in reducing OFF time and motor symptom severity, focusing on Unified Parkinson’s Disease Rating Scale (UPDRS) Part III scores in individuals with advanced PD.&#13;
Objectives: A systematic search of PubMed, Cochrane, and EBSCO Megafile databases was conducted through April 16, 2025, according to PRISMA guidelines. Randomized controlled trials (RCTs) evaluating Apomorphine infusion and reporting outcomes on OFF time and UPDRS Part III were included. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated with GRADE. Meta-analyses were performed using a random effects model.&#13;
Result: Eight studies (n = 458) met the inclusion criteria, of which five were eligible for meta-analysis. Apomorphine infusion significantly reduced OFF time compared to placebo (MD = -1.93 hours; 95\% CI: -2.91 to -0.95; low-certainty evidence), with minimal heterogeneity (I² = 0\%). A significant reduction was also observed in UPDRS Part III scores (MD = -19.11; 95\% CI: -25.54 to -12.68; very low-certainty evidence), although substantial heterogeneity was present (I² = 67.93\%).&#13;
Conclusion: This systematic review supports the efficacy of Apomorphine infusion in reducing OFF time and improving motor symptoms in individuals with advanced PD. Apomorphine infusion represents a treatment option, particularly for patient’s ineligible for surgical interventions. However, the overall certainty of evidence is limited by methodological heterogeneity and a small number of high-quality trials. Future studies should aim for standardized outcome measures, long-term comparisons with other device-aided therapies, and exploration</Abstract><AbstractLanguage>English</AbstractLanguage><Keywords>Parkinson’s Disease, dyskinesia, motor symptoms</Keywords><URLs><Abstract>https://jneuro.clsconf.com/admin/abstract?id=20</Abstract></URLs><References><ReferencesarticleTitle>References</ReferencesarticleTitle><ReferencesfirstPage>16</ReferencesfirstPage><ReferenceslastPage>19</ReferenceslastPage><References>Kouli A, Torsney KM, Kuan WL. Parkinsonand;rsquo;s Disease: Etiology, Neuropathology, and Pathogenesis. Parkinsonand;rsquo;s Disease: Pathogenesis and Clinical Aspects. 2018;1(1):3-26.Doi: https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1 and;nbsp;[Google Scholar] [PubMed]Magrinelli F, Picelli A, Tocco P, et al. Pathophysiology of Motor Dysfunction in Parkinsonand;rsquo;s Disease as the Rationale for Drug Treatment and Rehabilitation. Parkinsonand;rsquo;s Disease. 2016;2016(1):1-18. Doi: https://doi.org/10.1155/2016/9832839 [Google Scholar] [PubMed]Freitas ME, Hess CW, Fox SH. Motor Complications of Dopaminergic Medications in Parkinsonand;rsquo;s Disease. Seminars in neurology. 2017;37(2):147-157. Doi: https://doi.org/10.1055/s-0037-1602423 [Google Scholar] [PubMed]Koch J. Management of OFF Condition in Parkinson Disease. The mental health clinician. 2023;13(6):289-297. Doi: https://doi.org/10.9740/mhc.2023.12.289 [Google Scholar] [PubMed]Ch Wolters E. Deep Brain Stimulation and Continuous Dopaminergic Stimulation in Advanced Parkinsonand;rsquo;s Disease. Parkinsonism and;amp; Related Disorders. 2007;13:S18-S23. Doi: https://doi.org/10.1016/j.parkreldis.2007.06.006 [Google Scholar] [PubMed]Volkmann J, Albanese A, Antonini A, et al. Selecting Deep Brain Stimulation or Infusion Therapies in Advanced Parkinsonand;rsquo;s Disease: An Evidence-based Review. Journal of Neurology. 2013;260(11):2701-2714. Doi: https://doi.org/10.1007/s00415-012-6798-6 [Google Scholar] [PubMed]Li A, Guo H, Luo X, et al. Apomorphine?induced Activation of Dopamine Receptors Modulates FGF?2 Expression in Astrocytic Cultures and Promotes Survival of Dopaminergic Neurons. The FASEB Journal. 2006;20(8):1263-1265. Doi: https://doi.org/10.1096/fj.05-5510fje [Google Scholar] [PubMed]Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine Subcutaneous Infusion in Patients with Parkinsonand;rsquo;s Disease with Persistent Motor Fluctuations (TOLEDO): A Multicentre, Double-blind, Randomised, Placebo-controlled Trial. The Lancet Neurology. 2018;17(9):749-759. Doi: https://doi.org/10.1016/s1474-4422(18)30239-4 [Google Scholar] [PubMed]Katzenschlager R, Poewe W, Rascol O, et al. Long-term Safety and Efficacy of Apomorphine Infusion in Parkinsonand;rsquo;s Disease Patients with Persistent Motor Fluctuations: Results of the Open-label Phase of the TOLEDO Study. Parkinsonism and;amp; Related Disorders. 2021;83:79-85. Doi: https://doi.org/10.1016/j.parkreldis.2020.12.024 [Google Scholar] [PubMed]Henriksen T, Staines H. Continuous Subcutaneous Apomorphine Infusion in Parkinsonand;rsquo;s Disease: A Single-Center, Long-Term Follow-Up Study of the Causes for Discontinuation. Journal of Personalized Medicine. 2021;11(6):525. Doi: https://doi.org/10.3390/jpm11060525 [Google Scholar] [PubMed]Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinsonand;rsquo;s Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs. 2019;33(9):905-918. Doi: https://doi.org/10.1007/s40263-019-00661-z [Google Scholar] [PubMed]Hauser R, Isaacson S, Clinch T, The Tigan/Apokyn Study Investigators. Randomized, Placebo-controlled Trial of Trimethobenzamide to Control Nausea and Vomiting During Initiation and Continued Treatment with Subcutaneous Apomorphine Injection. Parkinsonism and Related Disorders. Published online August 2014. Doi: https://doi.org/10.1016/j.parkreldis.2014.08.010 [Google Scholar] [PubMed]Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. British Medical Journal. 2021;372(71). Doi: https://doi.org/10.1136/bmj.n71 [Google Scholar] [PubMed]Scanlon BK, Katzen HL, Levin BE, Singer C, Papapetropoulos S. A Formula for the Conversion of UPDRS-III Scores to Hoehn and Yahr Stage. Parkinsonism and;amp; Related Disorders. 2008;14(4):379-380. Doi: https://doi.org/10.1016/j.parkreldis.2007.09.010 [Google Scholar] [PubMed]Shulman, L.M., Gruber-Baldini, A.L., Anderson, K.E., Fishman, P.S., Reich, S.G. and Weiner, W.J. (2010) The Clinically Important Difference on the Unified Parkinsonand;rsquo;s Disease Rating Scale. Archives of Neurology, 67, 64-70. and;nbsp;Doi: https://doi.org/10.1001/archneurol.2009.295 [Google Scholar] [PubMed]Nayak L, Henchcliffe C. Rasagiline in treatment of Parkinsonand;rsquo;s disease. Neuropsychiatric disease and treatment. 2008;4(1):23-32.Doi: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515917/#:~:text=Rasagiline%20prevents%20dopamine%20metabolism%20irreversibly [Google Scholar] [PubMed]Medicom Medical Publishers. Opicapone: follow-up on the BIPARK I and II trials. Medical Conferences. Published August 27, 2019. Doi: https://conferences.medicom-publishers.com/content/conference-reports/2019-09-23-155054/? Clarke CE, Smitaa Patel, Ives N, et al. UK Parkinsonand;rsquo;s Disease Society Brain Bank Diagnostic Criteria. Nih.gov. Published August 2016. Doi: https://www.ncbi.nlm.nih.gov/books/NBK379754/ [Google Scholar]Sterne JAC, Savovi? J, Page MJ, et al. RoB 2: A Revised Tool for Assessing Risk of bias in Randomised Trials. BMJ. 2019;366(1):l4898. Doi: https://doi.org/10.1136/bmj.l4898 [Google Scholar] [PubMed]Cochrane. 9.5.2 Identifying and measuring heterogeneity. Cochrane.org. Published 2019. https://handbook-5-1.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm Cochrane. 10.4.3.1 Recommendations on Testing for Funnel Plot Asymmetry. Cochrane.org. Published 2019. https://handbook-5-1.cochrane.org/chapter_10/10_4_3_1_recommendations_on_testing_for_funnel_plot_asymmetry.htm Zeng L, Brignardello-Petersen R, Hultcrantz M, et al. GRADE guidelines 32: GRADE Offers Guidance on Choosing Targets of GRADE certainty of Evidence Ratings. Journal of Clinical Epidemiology. 2021;137:163-175. Doi: https://doi.org/10.1016/j.jclinepi.2021.03.026 [Google Scholar] [PubMed]Pahwa R, Koller WC, Trosch RM, Sherry JH. Subcutaneous Apomorphine in Patients with Advanced Parkinsonand;rsquo;s Disease: A Dose-escalation Study with Randomized, Double-blind, Placebo-controlled Crossover Evaluation of a Single Dose. Journal of the Neurological Sciences. 2007;258(1-2):137-143. Doi: https://doi.org/10.1016/j.jns.2007.03.013 [Google Scholar] [PubMed]Pfeiffer RF, Gutmann L, Hull KL, Bottini PB, Sherry JH. Continued Efficacy and Safety of Subcutaneous Apomorphine in Patients with Advanced Parkinsonand;rsquo;s Disease. Parkinsonism and;amp; Related Disorders. 2007;13(2):93-100. Doi: https://doi.org/10.1016/j.parkreldis.2006.06.012 [Google Scholar] [PubMed]Van Laar T, Jansen E, Essink A, Neef C, Oosterloo S, Roos R. A Double-blind Study of the Efficacy of Apomorphine and its Assessment in and;ldquo;offand;rdquo;-periods in Parkinsonand;rsquo;s Disease. Clinical Neurology and Neurosurgery. 1993;95:23-235. [Google Scholar] [PubMed]Dewey R, Hutton T, Lewitt P, Factor S. A Randomized, Double-blind, Placebo-Controlled Trial of Subcutaneously Injected Apomorphine for Parkinsonian Off-State Events. Arch Neurol. 2001;58:1385-1392. [Google Scholar] [PubMed]Nomoto M, Kubo S, Nagai M, et al. A Randomized Controlled Trial of Subcutaneous Apomorphine for Parkinson Disease. Clinical Neuropharmacology. 2015;38(6):241-247. Doi: https://doi.org/10.1097/wnf.0000000000000111 [Google Scholar] [PubMed]Isaacson SH, Espay AJ, Pahwa R, et al. Continuous, Subcutaneous Apomorphine Infusion for Parkinson Disease Motor Fluctuations: Results From the phase 3, Long-term, Open-label United States InfusON Study. Journal of Parkinson s Disease. Published online January 29, 2025. Doi: https://doi.org/10.1177/1877718x241310727 [Google Scholar] [PubMed]Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society Evidence-based Medicine Review: Update on Treatments for the Motor Symptoms of Parkinsonand;rsquo;s Disease. Movement Disorders. 2018;33(8):1248-1266. Doi: https://doi.org/10.1002/mds.27372 [Google Scholar] [PubMed]Lo C, Arora S, Lawton M, et al. A Composite Clinical Motor Score as a Comprehensive and Sensitive Outcome Measure for Parkinsonand;rsquo;s Disease. Journal of Neurology, Neurosurgery and;amp; Psychiatry. 2022;93(6):617-624. Doi: https://doi.org/10.1136/jnnp-2021-327880 [Google Scholar] [PubMed]Martinez-Martin P, Reddy P, Katzenschlager R, et al. EuroInf: A Multicenter Comparative Observational Study of Apomorphine and Levodopa Infusion in Parkinsonand;rsquo;s Disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2015;30(4):510-516. Doi: https://doi.org/10.1002/mds.26067and;nbsp; [Google Scholar] [PubMed]</References></References></Journal></Article></article>
