Efficacy and Safety of Safinamide vs Opicapone as Adjuvant to Levodopa Therapy in Elderly with Parkinson’s Disease: A Network Meta-Analysis

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Melissa Valentina Ariyanto
Maxwell Salvador Surya Atmaja


Introduction: Parkinson's disease (PD) becomes a significant health problem in the elderly. This chronic and progressive neurodegenerative disease needs to be treated with dopamine agonists as a gold standard. The use of adjuvant therapies like safinamide and opicapone was considered a promising option to achieve a better outcome. However, they not have been compared in randomized controlled trials.

Objective: To compare the efficacy and safety of safinamide and opicapone as adjuncts to levodopa therapy in PD treatment.

Method: This systematic review and network meta-analysis of randomized controlled trials were conducted based on the PRISMA NMA Checklist of Items. The outcome of this study was the evaluation of the efficacy (ON-time, OFF-time, Unified Parkinson’s Disease Rating Scale [UPDRS-III], and the 39-Item Parkinson’s Disease Questionnaire [PDQ-39]) and safety of safinamide and opicapone in PD. Effect sizes were analyzed using both pairwise and Bayesian network meta-analyses.         

Result:  Fourteen RCTs were included in this study. The efficacy analyses showed that safinamide (MD = 0.87 h, 95% CrI = 0.31 - 1.48) was superior in increasing total ON-time compared to opicapone (MD = 0.82 h, 95% CrI = 0.18 - 1.47). Safinamide also showed superiority in reducing OFF-time (MD =-1.33 h, 95% CrI =-2.45 - -0.196), UPDRS-III score (MD =-2.8, 95% CrI =-3.92 - -1.66), and PDQ-39 score (MD =-2.05, 95% CrI =-3.47 - -0.702). Safety analysis also showed that safinamide (OR = 1.04, 95% CrI = 0.83 - 1.3) is more tolerable for older patients than opicapone (OR = 1.32, 95% CrI = 0.95 - 1.81).

Conclusion: In conclusion, our findings support the use of safinamide in elderly patients with PD, which effectively helps levodopa improve ON-time, better tolerating motor and non-motor features during the OFF period, and increasing the quality of life with minimal adverse effects.

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Aldian, F. M., Ariyanto, M. V., Atmaja, M. S. S. and Vissudho (2023) “Efficacy and Safety of Safinamide vs Opicapone as Adjuvant to Levodopa Therapy in Elderly with Parkinson’s Disease: A Network Meta-Analysis ”, Journal of Asian Medical Students’ Association. Kuala Lumpur, Malaysia. Available at: https://jamsa.amsa-international.org/index.php/main/article/view/623 (Accessed: 21May2024).
Scientific Papers (AMSC 2023 Taiwan)


Balestrino R, Schapira AHV. Parkinson disease. European Journal of Neurology 2019;27:27–42. doi:10.1111/ene.14108.

Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of parkinson's disease: A systematic review and meta-analysis. Movement Disorders 2014;29:1583–90. doi:10.1002/mds.25945.

Marino BLB, de Souza LR, Sousa KPA, Ferreira JV, Padilha EC, da Silva CHTP, et al. Parkinson’s disease: A review from pathophysiology to treatment. Mini-Reviews in Medicinal Chemistry 2020;20:754–67. doi:10.2174/1389557519666191104110908.

Kim H-S, Cheon S-M, Seo J-W, Ryu H-J, Park K-W, Kim JW. Nonmotor symptoms more closely related to parkinson's disease: Comparison with normal elderly. Journal of the Neurological Sciences 2013;324:70–3. doi:10.1016/j.jns.2012.10.004.

Pfeiffer RF. Non-motor symptoms in parkinson's disease. Parkinsonism & Related Disorders 2016;22. doi:10.1016/j.parkreldis.2015.09.004.

Mirpour S, Turkbey EB, Marashdeh W, El Khouli R, Subramaniam RM. Impact of DAT-SPECT on management of patients suspected of parkinsonism. Clinical Nuclear Medicine 2018;43:710–4. doi:10.1097/rlu.0000000000002240.

Lill CM, Klein C. Epidemiologie und ursachen der parkinson-erkrankung. Der Nervenarzt 2017;88:345–55. doi:10.1007/s00115-017-0288-0.

WHO. Parkinson disease. World Health Organization 2022.

https://www.who.int/news-room/fact-sheets/detail/parkinson-disease#:~:text=Overvie w-,Parkinson%20disease%20(PD)%20is%20a%20degenerative%20condition%20of% 20the%20brain,pain%20and%20other%20sensory%20disturbances).

Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of parkinson disease. Canadian Medical Association Journal 2016;188:1157–65. doi:10.1503/cmaj.151179.

Kassandra F. Hubungan Antara Penggunaan Obat Anti Hipertensi dan Penyakit Parkinson di Rumah Sakit Bethesda Yogyakarta; 2017.

Lampropoulos IC, Malli F, Sinani O, Gourgoulianis KI, Xiromerisiou G. Worldwide trends in mortality related to parkinson's disease in the period of 1994–2019: Analysis of vital registration data from the Who Mortality Database. Frontiers in Neurology 2022;13. doi:10.3389/fneur.2022.956440.

Farombi TH, Owolabi MO, Ogunniyi A. Falls and their associated risks in parkinson's disease patients in Nigeria. Journal of Movement Disorders 2016;9:160–5. doi:10.14802/jmd.16011.

Schini M, Bhatia P, Shreef H, Johansson H, Harvey NC, Lorentzon M, et al. Increased fracture risk in parkinson's disease – an exploration of mechanisms and consequences

for fracture prediction with frax. Bone 2023;168:116651. doi:10.1016/j.bone.2022.116651.

Albarmawi H, Zhou S, Shulman LM, Gandhi AB, Johnson A, Myers DE, et al. The economic burden of parkinson disease among Medicare beneficiaries. Journal of Managed Care & Specialty Pharmacy 2022;28:405–14. doi:10.18553/jmcp.2022.28.4.405.

Yang W, Hamilton JL, Kopil C, Beck JC, Tanner CM, Albin RL, et al. Current and projected future economic burden of parkinson’s disease in the U.S. Npj Parkinson's Disease 2020;6. doi:10.1038/s41531-020-0117-1.

Belvisi D, Pellicciari R, Fabbrini A, Costanzo M, Pietracupa S, De Lucia M, et al. Risk factors of parkinson disease. Neurology 2020;95. doi:10.1212/wnl.0000000000010813.

LeWitt PA. Levodopa therapy for parkinson's disease: Pharmacokinetics and pharmacodynamics. Movement Disorders 2014;30:64–72. doi:10.1002/mds.26082.

Tambasco N, Romoli M, Calabresi P. Levodopa in parkinson’s disease: Current status and future developments. Current Neuropharmacology 2018;16:1239–52. doi:10.2174/1570159x15666170510143821.

Charvin D, Medori R, Hauser RA, Rascol O. Therapeutic strategies for parkinson disease: Beyond dopaminergic drugs. Nature Reviews Drug Discovery 2018;17:804–22. doi:10.1038/nrd.2018.136.

Salat D, Tolosa E. Levodopa in the treatment of parkinson's disease: Current status and new developments. Journal of Parkinson's Disease 2013;3:255–69. doi:10.3233/jpd-130186.

Hauser RA, LeWitt PA, Comella CL. On demand therapy for parkinson’s disease patients: Opportunities and choices. Postgraduate Medicine 2021;133:721–7. doi:10.1080/00325481.2021.1936087.

Fox SH. Non-dopaminergic treatments for motor control in parkinson’s disease. Drugs 2013;73:1405–15. doi:10.1007/s40265-013-0105-4.

Sampaio TF, dos Santos EU, de Lima GD, dos Anjos RS, da Silva RC, Asano AG, et al. MAO-bandcomtgenetic variations associated with levodopa treatment response in patients with parkinson's disease. The Journal of Clinical Pharmacology 2018;58:920–6. doi:10.1002/jcph.1096.

Pahwa R, Lyons KE. Treatment of early parkinson's disease. Current Opinion in Neurology 2014;27:442–9. doi:10.1097/wco.0000000000000113.

Greenwood J, Pham H, Rey J. Opicapone: A third generation COMT inhibitor. Clinical Parkinsonism & Related Disorders 2021;4:100083. doi:10.1016/j.prdoa.2020.100083.

Bette S, Shpiner DS, Singer C, Moore H. Safinamide in the management of patients with parkinson’s disease not stabilized on levodopa: A review of the current clinical evidence. Therapeutics and Clinical Risk Management 2018;Volume 14:1737–45. doi:10.2147/tcrm.s139545

Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catalá-López F, Gøtzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and Explanations. Ann Intern Med. 2015;162(11):777-784.

Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.

Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: A comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Services Research. 2014;14(1).

Europe P. Wearing off and motor fluctuations [Internet]. Wearing off and motor fluctuations | Parkinson's Europe. Available from: https://www.parkinsonseurope.org/

Olanow CW, Poewe W, Rascol O, Stocchi F. on‐demand therapy for off episodes in parkinson's disease. Movement Disorders. 2021;36(10):2244–53.

Sánchez-Ferro Á, Matarazzo M, Martínez-Martín P, Martínez-Ávila JC, Gómez de la Cámara A, Giancardo L, et al. Minimal clinically important difference for UPDRS-III in daily practice. Movement Disorders Clinical Practice. 2018;5(4):448–50.

Cattaneo C, Jost WH, Bonizzoni E. Long-term efficacy of safinamide on symptoms severity and quality of life in fluctuating parkinson’s disease patients. Journal of Parkinson's Disease. 2020;10(1):89–97

Unified Parkinson Disease Rating Scale (UPDRS) [Internet]. Theracycle Physical Therapy Exercise Bike and Rehabilitation Equipment. Available from: https://www.theracycle.com/

Parkinson's disease questionnaire - 39 [Internet]. Shirley Ryan AbilityLab. Available from: https://www.sralab.org/

The parkinson's disease questionnaire (PDQ-39) [Internet]. Parkinson's UK. 2020. Available from: https://www.parkinsons.org.uk/.

Martinez-Martin P, Rodriguez-Blazquez C, Forjaz MJ, Kurtis MM. Impact of pharmacotherapy on quality of life in patients with parkinson’s disease. CNS Drugs. 2015;29(5):397–413.

Sterne JAC, SavovićJ, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool forassessing risk of bias in randomised trials. BMJ. 2019; 366: 1–8. https://doi.org/10.1136/bmj.l4898PMID: 31462531.

Rücker G, Schwarzer G, Krahn U, König J netmeta: Network Meta-Analysis using Frequentist Methods (R package version 0.9-5). https://CRANR-projectorg/ package=netmeta 2017.

Dias S, Sutton AJ, Ades AE, et al. Evidence synthesis for decision making 2: A generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Mak. 2013;33:607–17.

Owen, RK, Bradbury, N, Xin, Y, Cooper, N, Sutton, A. MetaInsight: An interactive web-based tool for analyzing, interrogating, and visualizing network meta-analyses using R-shiny and netmeta. Res Syn Meth. 2019; 10: 569-581.

Higgins JPT, Jackson D, Barrett JK, et al. Consistency and inconsistency in network meta-analysis: concepts and models for multiarm studies. Res Synth Methods. 2012;3:98–110.

van Valkenhoef G, Tervonen T, de Brock B, et al. Algorithmic parameterization of mixed treatment comparisons. Stat Comput. 2012;22:1099–111.

Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M & Salanti G. CINeMA: An approach for assessing confidence in the results of a network meta-analysis PLOS Medicine 2020 17 1-19

Papakonstantinou T, Nikolakopoulou A, Higgins JPT, Egger M & Salanti G. CINeMA: Software for semiautomated assessment of the confidence in the results of network meta-analysis Campbell Systematic Reviews 2020 16 e1080

Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP. Evaluating the quality of evidence from a network meta-analysis. PLoS One. 2014;9:e99682.

Nevill CR, Cooper NJ, Sutton AJ, A multifaceted graphical display, including treatment ranking, was developed to aid interpretation of network meta-analysis, Journal of Clinical Epidemiology (2023)

Daly CH, Neupane B, Beyene J, et al. Empirical evaluation of SUCRA-based treatment ranks in network Meta-analysis: quantifying robustness using cohen’s kappa. BMJ Open. 2019;9(9):e024625.

Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159:130–7.

Kulisevsky J, Martínez-Horta S, Campolongo A, Pascual-Sedano B, Marín-Lahoz J, Bejr-kasem H, et al. A randomized clinical trial to evaluate the effects of safinamide on apathetic non-demented patients with parkinson's disease. Frontiers in Neurology. 2022;13.

Stocchi F, Borgohain R, Onofrj M, Schapira AHV, Bhatt M, Lucini V, et al. A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early parkinson's disease patients. Movement Disorders. 2011;27(1):106–12.

Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with parkinson disease and motor fluctuations. JAMA Neurology. 2017;74(2):216.

Nomoto M, Ishida T, Koebis M, Kamei T, Suzuki I, Hattori N, et al. Characteristics of wearing-off and motor symptoms improved by Safinamide adjunct therapy in patients with parkinson's disease: A post hoc analysis of a Japanese phase 2/3 study. Journal of the Neurological Sciences. 2022;434:120083.

Hattori N, Tsuboi Y, Yamamoto A, Sasagawa Y, Nomoto M. Efficacy and safety of safinamide as an add-on therapy to L-DOPA for patients with parkinson's disease: A randomized, double-blind, placebo-controlled, phase II/III study. Parkinsonism & Related Disorders. 2020;75:17–23.

Schapira AH, Stocchi F, Borgohain R, Onofrj M, Bhatt M, Lorenzana P, et al. Long-term efficacy and safety of safinamide as add-on therapy in early parkinson's disease. European Journal of Neurology. 2012;20(2):271–80.

Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, et al. Randomized trial of Safinamide add‐on to levodopa in parkinson's disease with motor fluctuations. Movement Disorders. 2013;29(2):229–37.

Wei Q, Tan Y, Xu P, Tao E, Lu Z, Pan X, et al. The Xindi Study: A randomized phase III clinical trial evaluating the efficacy and safety of safinamide as add-on therapy to levodopa in Chinese patients with parkinson’s disease with motor fluctuations. CNS Drugs. 2022;36(11):1217–27.

Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt MH, Chirilineau D, et al. Two‐year, randomized, controlled study of Safinamide as add‐on to levodopa in mid to late parkinson's disease. Movement Disorders. 2014;29(10):1273–80.

Ferreira JJ, Rocha J-F, Falcão A, Santos A, Pinto R, Nunes T, et al. Effect of opicapone on levodopa pharmacokinetics, catechol-o-methyltransferase activity and motor fluctuations in patients with parkinson's disease. European Journal of Neurology. 2015;22(5).

Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares‐da‐Silva P. Long‐term efficacy of opicapone in fluctuating parkinson's disease patients: A pooled analysis of data from two phase 3 clinical trials and their open‐label extensions. European Journal of Neurology. 2019;26(7):953–60.

Lees AJ, Ferreira J, Rascol O, Poewe W, Rocha J-F, McCrory M, et al. Opicapone as adjunct to levodopa therapy in patients with parkinson disease and motor fluctuations. JAMA Neurology. 2017;74(2):197.

Ferreira JJ, Lees A, Rocha J-F, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with parkinson's disease and end-of-dose motor fluctuations: A randomised, double-blind, controlled trial. The Lancet Neurology. 2016;15(2):154–65.

Takeda A, Takahashi R, Tsuboi Y, Nomoto M, Maeda T, Nishimura A, et al. Randomized, controlled study of Opicapone in Japanese parkinson's patients with motor fluctuations. Movement Disorders. 2020;36(2):415–23.

Full prescribing information: Contents* - food and drug administration [Internet]. Available from:


Reference ID: 4072731 - food and drug administration [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207145lbl.pdf

Kaakkola S. Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. doi: 10.2165/00003495-200059060-00004.

Almeida L, Rocha JF, Falcao A, Palma PN, Loureiro AI, Pinto R, Bonifacio MJ, Wright LC, Nunes T, Soares-da-Silva P: Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor. Clin Pharmacokinet. 2013 Feb;52(2):139-51. doi: 10.1007/s40262-012-0024-7.

Mancini F, Di Fonzo A, Lazzeri G, Borellini L, Silani V, Lacerenza M, et al. Real life evaluation of safinamide effectiveness in parkinson’s disease. Neurological Sciences. 2018;39(4):733–9.

Cattaneo C, Müller T, Bonizzoni E, Lazzeri G, Kottakis I, Keywood C. Long-term effects of safinamide on mood fluctuations in parkinson’s disease. Journal of Parkinson's Disease. 2017;7(4):629–34.

Antonini A, Marano P, Gusmaroli G, Modugno N, Pacchetti C, Sensi M, Melzi G, Bergmann L, Zibetti M, Lopiano L. Long-term effectiveness of levodopa-carbidopa intestinal gel on motor and non-motor symptoms in advanced Parkinson's disease: results of the Italian GLORIA patient population. Neurol Sci. 2020 Oct;41(10):2929-2937. doi: 10.1007/s10072-020-04401-w. Epub 2020 Apr 28.

Żegleń M, Śladowska K, Kawalec P, Brzostek T. Opicapone as an add-on to levodopa for reducing end-of-dose motor fluctuations in parkinson’s disease: A systematic review and meta-analysis. Journal of Comparative Effectiveness Research. 2022;11(12):889–904.

Giossi R, Carrara F, Mazzari M, Lo Re F, Senatore M, Schicchi A, et al. Overall efficacy and safety of safinamide in parkinson’s disease: A systematic review and a meta-analysis. Clinical Drug Investigation. 2021;41(4):321–39.

Tsuboi Y, Hattori N, Yamamoto A, Sasagawa Y, Nomoto M. Long-term safety and efficacy of safinamide as add-on therapy in levodopa-treated Japanese patients with parkinson's disease with wearing-off: Results of an open-label study. Journal of the Neurological Sciences. 2020;416:117012.

Takeda A, Takahashi R, Tsuboi Y, Nomoto M, Maeda T, Nishimura A, et al. Long-term safety and efficacy of opicapone in Japanese parkinson’s patients with motor fluctuations. Journal of Neural Transmission. 2021;128(3):337–44.

Svetel M, Tomić A, Kresojević N, Kostić V. Pharmacokinetic drug evaluation of opicapone for the treatment of Parkinson's disease. Expert Opin Drug Metab Toxicol. 2018 Mar;14(3):353-360. doi: 10.1080/17425255.2018.1430138. Epub 2018 Jan 24. PMID: 29345156.

Ross, MSc candidate SB, Wu PE, Atique, MD candidate A, Papillon‐Ferland L, Tamblyn R, Lee TC, et al. Adverse drug events in older adults: Review of Adjudication Methods in deprescribing studies. Journal of the American Geriatrics Society 2020;68:1594–602. doi:10.1111/jgs.16382.

Azevedo Kauppila L, Pimenta Silva D, Ferreira JJ. Clinical utility of opicapone in the management of sparkinson's disease: A short review on emerging data and place in therapy. Degenerative Neurological and Neuromuscular Disease 2021;Volume 11:29–40. doi:10.2147/dnnd.s256722.

Rinaldi D, Bianchini E, Sforza M, Alborghetti M, Galli S, Salvetti M, et al. The tolerability, safety and efficacy of safinamide in elderly parkinson's disease patients: A retrospective study. Aging Clinical and Experimental Research 2020;33:1689–92. doi:10.1007/s40520-020-01648-3.

Lo Monaco MR, Petracca M, Vetrano DL, Di Stasio E, Fusco D, Ricciardi D, et al. Safinamide as an adjunct therapy in older patients with parkinson's disease: A retrospective study. Aging Clinical and Experimental Research 2020;32:1369–73. doi:10.1007/s40520-020-01469-4.


Amanda. Xadago (safinamide) is now available in the USA for parkinson's disease patients. NeuroNews International 2017.

https://neuronewsinternational.com/xadago-safinamide-now-available-in-the-usa-for-p arkinsons-disease-patients/.

Deeks ED. Safinamide: First global approval. Drugs 2015;75:705–11. doi:10.1007/s40265-015-0389-7.

Koebisu M, Ishida T. Safinamide mesilate (equfina® tablets 50 mg): Preclinical and clinical pharmacodynamics, efficacy, and safety. Folia Pharmacologica Japonica 2020;155:269–76. doi:10.1254/fpj.20012.

AH S, R B, D SG, YH H, HA B, N H, et al. Safinamide. ALZFORUM 2021. https://www.alzforum.org/therapeutics/safinamide (accessed April 3, 2023).

Lowin J, Bergman A, Ray Chaudhuri K, Findley LJ, Roeder C, Schifflers M, et al. A cost-effectiveness analysis of levodopa/carbidopa intestinal gel compared to standard care in late stage parkinson’s disease in the UK. Journal of Medical Economics. 2011;14(5):584–93.

Ongentys prices, coupons, Copay & Patient Assistance [Internet]. Drugs.com. Available from: https://www.drugs.com/price-guide/ongentys

Kabisch M, Ruckes C, Seibert-Grafe M, Blettner M. Randomized Controlled Trials. Deutsches Ärzteblatt international. 2011;