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Letter to the editor
Investigation of the Long-Term Effects of Amantadine Use in Parkinson’s Disease -
Sangmin Park1
, Jung Hwan Shin2, Seung Ho Jeon3, Chan Young Lee4, Han-Joon Kim2, Beomseok Jeon2
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Journal of Movement Disorders 2023;16(2):224-226.
DOI: https://doi.org/10.14802/jmd.23037
Published online: May 24, 2023
1Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea
2Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
3Eco Fineday Neurology Clinic, Jeonju, Korea
4Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea
- Corresponding author: Beomseok Jeon, MD, PhD Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea / Tel: +82-2-2072-2876 / Fax: +82-2-3672-7553 / E-mail: brain@snu.ac.kr
• Received: February 20, 2023 • Revised: March 14, 2023 • Accepted: March 21, 2023
Copyright © 2023 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Dear Editor,
Amantadine has been used for the symptomatic treatment of Parkinson’s disease (PD) as monotherapy, adjuvant therapy, or as an anti-dyskinetic agent. However, amantadine has been known to be ineffective in the later months, and the effects on motor fluctuation or nonmotor symptoms are unclear [1-3]. This study aimed to examine whether amantadine is effective long-term in PD.
Previously, we examined whether amantadine could prevent the development of dyskinesia in drug-naïve PD patients in a prospective randomized study (ClinicalTrials.gov, Identifier number NCT01338662) [4]. In that 3-year study, 38 of 54 drugnaïve patients who were started on amantadine completed the study. Of the 38 patients, 32 remained in the clinic after 5 additional years. Two patients refused to participate in the study. Thus, 30 patients who were on amantadine for 8 years were enrolled in the study (Supplementary Figure 1 in the online-only Data Supplement).
This study was a prospective open-label pragmatic trial. The participants were instructed to stop taking amantadine. Clinical evaluations were repeated at the 4- and 8-week follow-ups. 1) If they had withdrawal symptoms, they contacted the movement disorder center immediately and were interviewed over the phone by the neurologists for the details of the withdrawal symptoms. Considering the half-life (10 to 14 hours) of amantadine, symptoms that occurred one day after amantadine discontinuation were defined as withdrawal symptoms. After the interview, the patients resumed amantadine to see whether they recovered. Patients were then asked to stop amantadine again one day before the scheduled visit and were then examined. 2) If they did not deteriorate, they were asked to discontinue amantadine. Baseline information, including the age of onset, PD duration, sex, amantadine therapy duration, levodopa equivalent daily dose (LEDD), the Korean version of the Montreal Cognitive Assessment score, the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score, the Nonmotor Symptom Scale score, and the Parkinson’s Disease Questionnaire 39 summary index score, were all obtained at the beginning of the study. All assessments and clinical evaluations were performed in the on-medication state (Supplementary Figure 1 in the online-only Data Supplement).
Data were analyzed using the Statistical Package for Social Sciences (SPSS) ver. 21 (IBM Corp., Armonk, NY, USA). Descriptive statistics (mean and standard deviation) were computed for all the outcome variables, wherein data were expressed as the number and percentage of patients with withdrawal symptoms following amantadine discontinuation. Differences in clinical characteristics between baseline and the discontinuation period were analyzed using the Wilcoxon signed rank test. The statistical threshold was set at p < 0.05 for all analyses.
Supplementary Table 1 (in the online-only Data Supplement) shows the demographic and clinical characteristics of the 30 patients. The average age was 51.1 years; the average disease duration was 9.6 years; and the average duration of amantadine administration was 7.9 years. The average LEDD and dosage of amantadine were 934.8 and 293.3 mg/d, respectively, the MDS-UPDRS Part III score was 28.9, and the Hoehn-Yahr stage was 2 for the on-medication state (Supplementary Table 1 in the online-only Data Supplement).
Twenty-four of the 30 patients reported worsening in various motor symptoms, such as tremor, clumsiness, stiffness, or gait disturbance, and in nonmotor symptoms, especially pain and general weakness, within approximately 3.6 days of discontinuing amantadine (Table 1). They had to take amantadine again due to worsening symptoms. Twenty-two patients achieved a full recovery; however, two patients achieved only partial recovery. During the discontinuation period, two developed dyskinesia, and two developed motor fluctuation. At the 4-week follow-up, 24 patients who resumed amantadine because of worsening were asked to stop amantadine for 1 day before the visit, and the MDS-UPDRS part III score for the on-medication state was significantly worsened from baseline (30.0 ± 12.8 vs. 33.3 ± 14.3, p = 0.029).
However, six patients reported no worsening after stopping amantadine for up to eight weeks. In fact, two patients reported subjective improvement in motor symptoms, and one patient reported improvement in sleep problems and constipation.
Twenty-four of 30 patients who had been taking amantadine for approximately eight years reported worsening of various motor and nonmotor symptoms after discontinuing amantadine, which improved after the reintroduction of amantadine. The occurrence of dyskinesia and motor fluctuation during the discontinuation period suggests that amantadine has anti-dyskinetic and long-duration effects [5,6]. Several studies have reported that amantadine is effective for nonmotor symptoms such as apathy, fatigue, and pain [6,7]. However, there is insufficient evidence of this efficacy, as in the evidence-based medicine review [3]. Thus, more studies are needed to support the effectiveness of amantadine in nonmotor symptoms. Six patients reported no worsening after discontinuing amantadine, suggesting that amantadine may not be effective in some patients.
This study had several limitations. First, our study was an open-label and not a placebo-controlled study, and thus, the placebo or nocebo effect could not be ruled out. Second, selection bias might have been caused by patients who were dropped from the initial study. Third, patients were interviewed by phone at the patients’ convenience and not examined when they developed withdrawal symptoms. Even though they discontinued amantadine for one day prior to the visit to evaluate their motor score, one day may not have been enough to see the full deterioration. In the future, it is necessary to address these limitations to demonstrate the long-term effects of amantadine.
Amantadine may have long-term effects given the diverse withdrawal symptoms. However, discontinuation of amantadine may be considered to examine whether amantadine is effective, because it is ineffective in some patients.
Supplementary Material
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.23037.
Supplementary Table 1.
Baseline demographic and clinical characteristics of PD patients (n = 30)
Supplementary Figure 1.
Flowchart of trail process. MSA-P, multiple system atrophy-parkinsonian type.
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Ethics Statement
All patients signed a written informed consent form in accordance with the 2013 Declaration of Helsinki. The objectives and procedures of the study were approved by the Seoul National University Hospital Institutional Review Board (1909-072-106).
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
This research was supported by a grant from the Seoul National University Hospital Fund (30-2020-0010).
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Author Contributions
Conceptualization: Sangmin Park, Beomseok Jeon. Methodology: Sangmin Park, Beomseok Jeon. Funding acquisition: Beomseok Jeon. Supervision: Beomseok Jeon. Project administration: Sangmin Park, Beomseok Jeon. Investigation: Sangmin Park, Jung Hwan Shin, Seung Ho Jeon, Chan Young Lee. Data curation: Sangmin Park, Jung Hwan Shin, Seung Ho Jeon, Chan Young Lee, Han-Joon Kim, Beomseok Jeon. Formal analysis: Sangmin Park. Writing—original draft: Sangmin Park. Writing—review & editing: Jung Hwan Shin, Seung Ho Jeon, Chan Young Lee, Han-Joon Kim, Beomseok Jeon.
Notes
Table 1.
Withdrawal symptoms after discontinuation of amantadine (n = 24)
- 1. Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M. Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004;75:141–143.PubMedPMC
- 2. Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie RMA, Seppi K, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2018;33:1248–1266.ArticlePubMedPDF
- 3. Seppi K, Ray Chaudhuri K, Coelho M, Fox SH, Katzenschlager R, Perez Lloret S, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease-an evidence‐based medicine review. Mov Disord 2019;34:180–198.ArticlePubMedPMCPDF
- 4. Kim A, Kim YE, Yun JY, Kim HJ, Yang HJ, Lee WW, et al. Amantadine and the risk of dyskinesia in patients with early Parkinson’s disease: An Open-Label, Pragmatic Trial. J Mov Disord 2018;11:65–71.ArticlePubMedPMCPDF
- 5. Ory-Magne F, Corvol JC, Azulay JP, Bonnet AM, Brefel-Courbon C, Damier P, et al. Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 2014;82:300–307.ArticlePubMed
- 6. Wolf E, Seppi K, Katzenschlager R, Hochschorner G, Ransmayr G, Schwingenschuh P, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson’s disease. Mov Disord 2010;25:1357–1363.ArticlePubMedPDF
- 7. Pucci E, Branãs P, D’Amico R, Giuliani G, Solari A, Taus C. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007;CD002818. Article
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Investigation of the Long-Term Effects of Amantadine Use in Parkinson’s Disease
Investigation of the Long-Term Effects of Amantadine Use in Parkinson’s Disease
| Withdrawal symptoms | Values |
|---|---|
| Motor symptom | |
| Tremor | 9 (37.5) |
| Clumsiness | 6 (25.0) |
| Gait disturbance | 6 (25.0) |
| Stiffness | 5 (20.8) |
| Motor complication | |
| Wearing off | 2 (8.3) |
| Dyskinesia | 2 (8.3) |
| Off dystonia | 1 (4.2) |
| Non-motor symptom | |
| Pain | 6 (25.0) |
| General weakness | 6 (25.0) |
| Paresthesia | 2 (8.3) |
| Edema | 2 (8.3) |
| Fatigue | 2 (8.3) |
| Apathy | 1 (4.2) |
| Sialorrhea | 1 (4.2) |
| Palpitation | 1 (4.2) |
| Depressive mood | 1 (4.2) |
| Dizziness | 1 (4.2) |
| Anxiety | 1 (4.2) |
Table 1. Withdrawal symptoms after discontinuation of amantadine (n = 24)
Values are presented as
