https://orcid.org/0009-0004-8690-3151
Figures
Abstract
Background
Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson’s disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice.
Methods
We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS.
Results
Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs.
Citation: Nomoto M, Tsuboi Y, Kashihara K, Chiu S-W, Maeda T, Saiki H, et al. (2024) Prescription trends in Japanese advanced Parkinson’s disease patients with non-motor symptoms: J-FIRST. PLoS ONE 19(10): e0309297. https://doi.org/10.1371/journal.pone.0309297
Editor: Calogero Edoardo Cicero, University of Catania Department of Surgical and Medical Sciences Advanced Technologies GF Ingrassia: Universita degli Studi di Catania Dipartimento di Scienze Mediche Chirurgiche e Tecnologie Avanzate GF Ingrassia, ITALY
Received: January 29, 2024; Accepted: August 1, 2024; Published: October 23, 2024
Copyright: © 2024 Nomoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: At the start of this study, the informed consent forms did not explicitly stipulate data sharing for research purposes, and patient consent was not obtained to share data publicly. From the perspective of protecting patient confidentiality and in accordance with current Japanese laws and guidelines (Personal Information Protection Act, Ethical Guidelines for Life Science and Medical Research Involving Human Subjects, and Clinical Trials Act), the datasets generated during and/or analyzed during the current study are not publicly available. However, data may be shared upon reasonable request. For further information about data sharing, please contact the Medical Affairs Department at Kyowa Kirin Co., Ltd., Tokyo, Japan (ma.cns.fs@kyowakirin.com).
Funding: This study and medical writing support funded by Kyowa Kirin Co., Ltd (no grant number applies) to MN, YT, KK, SWC, TM, HS, HW, YS, NH, and TY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Masahiro Nomoto reported research funds from Kyowa Kirin in relation to this study; and reported employment by The Social Welfare Organization Imperial Gift Foundation Inc. Saiseikai Imabari Hospital; honoraria from Ehime University, Takeda Pharmaceutical, Kyowa Kirin, Eisai, and Ono Pharmaceutical; consultancies for Kissei Pharmaceutical and SNLD; and has served on advisory boards for the Pharmaceuticals and Medical Devices Agency and Ehime Prefecture. Yoshio Tsuboi reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees from Sumitomo Pharma, Takeda Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, and Eisai; and contributes to courses organized by SUNWELS and Nipro Corporation. Kenichi Kashihara reported research funds from Kyowa Kirin in relation to this study; and reported employment by Okayama Neurology Clinic; and honoraria from Kyowa Kirin, Takeda Pharmaceutical, Ono Pharmaceutical, Sumitomo Pharma, FP Corporation, AbbVie GK, and Eisai. Shih-Wei Chiu reported research funds from Kyowa Kirin in relation to this study. Tetsuya Maeda reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees and scholarship donations from Sumitomo Pharma, Takeda Pharmaceutical Company, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, Nippon Boehringer Ingelheim, Daiichi Sankyo, and Japan Medtronic; lecture fees from AbbVie, FP Corporation, Biogen, and Chugai Pharmaceutical; scholarship donations from Bayer Yakuhin, Teijin, and CSL Behring; and consulting fees from Kyowa Kirin and Ono Pharmaceutical. Hidemoto Saiki reported editorial support from Kyowa Kirin in relation to this study; and reported honoraria from Eisai, Sumitomo Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, and Medtronic Japan; and grants from Otsuka Pharmaceutical and PDRadiopharma Inc. Hirohisa Watanabe reported research funds from Kyowa Kirin in relation to this study; and reported honoraria from Takeda Pharmaceutical, AbbVie, Kyowa Kirin, Sumitomo Pharma, Novartis Pharma, Otsuka Pharmaceutical, and FP Corporation. Yasushi Shimo reported honoraria from Takeda Pharmaceutical, Abbott Japan, Otsuka Pharmaceutical, Medtronic Japan, Kyowa Kirin, Eisai, MDS, Boston Scientific Japan, Sumitomo Pharma, Daiichi Sankyo, Nihon Medi-Physics, and EA Pharma; and a grant from Japan Society for the Promotion of Science (JSPS KAKENHI no. 21K07282). Nobutaka Hattori reported research grants, support for attending advisory boards, and support for a joint research department from Kyowa Kirin; and reported research contracts with Sumitomo Pharma and CellSource; consultancy fees from PARKINSON Laboratories; honoraria from Sumitomo Pharma, AbbVie, Otsuka Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, FP Pharmaceutical, Eisai, and Daiichi Sankyo; support for attending advisory boards from Sumitomo Pharma, Novartis Pharma, Ono Pharmaceutical, Teijin Pharma, and Mitsubishi Tanabe Pharma Corporation; support for an endowed department from Nippon Boehringer Ingelheim, FP Pharmaceutical, Teijin Pharma, Fujifilm Wako Pure Chemical Corporation, and Meiji Seika Pharma; support for a joint research department from Kyowa Kirin, Sumitomo Pharma, Parkinson Laboratories, Takeda Pharmaceutical, Otsuka Pharmaceutical, Ono Pharmaceutical, Nihon Medi-Physics, Mitsubishi Tanabe Pharma Corporation, and Sunwels; scholarship donations from FP Pharmaceutical; holds stock in Parkinson Laboratories; honoraria for a team leader role at RIKEN Center for Brain Science; and is a coauthor on patent applications by Juntendo University. Takuhiro Yamaguchi reported grants from Otsuka Pharmaceutical, Solasia Pharma, Japan Tobacco Inc., Daiichi Sankyo, Eisai, and Cordis Corporation; and personal fees from Intellim Corporation, Chugai Pharmaceutical, SONIRE Therapeutics Inc., Merck and Co Inc., EPS Corporation, Japan Tobacco Inc., Ono Pharmaceutical, Kowa Company, Daiichi Sankyo, Eisai, 3H Clinical Trial Inc., and Incyte Biosciences Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
Patients with Parkinson’s disease (PD) often exhibit a range of motor symptoms, such as wearing-off and dyskinesia, that are primarily caused by chronic levodopa therapy and have a significant impact on the patient’s daily activities and quality of life [1, 2]. Many patients also develop non-motor symptoms (NMS), such as pain, cognitive symptoms, neuropsychiatric symptoms, sensory symptoms, sleep disorders, and autonomic symptoms, that also contribute to the deteriorations in quality of life [3–6]. Thus, it is important for physicians to consider not only the motor symptoms but also the NMS in the care of patients with PD.
The clinical guidelines for PD currently contain limited evidence regarding the use of medications to manage NMS and only describe medications based on experience [7]. Furthermore, there are limited data on the best practices for the pharmacological treatment of PD encompassing the treatment of NMS. Accordingly, there is a clear need to obtain more data, particularly in real-world settings, regarding the use of appropriate medications for NMS.
Some studies have attempted to analyze the real-world treatment of PD in Japan, including recent analyses of health insurance claims data using the Japanese Medical Data Vision database, for example [8, 9]. Although such studies provide a snapshot of recent treatment practices, they contained limited data on disease severity and NMS burden, which should influence treatment practices. Therefore, studies using prospectively collected data in clinical practice can help to investigate the therapies prescribed by physicians in the real world.
We should also consider the possibility that treatment practices may vary among clinical institutions and regions. Indeed, geographical variability in prescribing practices has been reported in other countries/continents that may reflect differences in national guidelines or an urban–rural divide [10–12]. In particular, in a European study, the use of anti-PD drugs (calculated as the defined daily dose per 1000 inhabitants daily) increased between 2003 and 2007, but there were clear differences in this measure, as well as the use of specific drug classes, among the countries evaluated in that study [12].
Some anti-PD drugs are used to treat the NMS of PD, but they can sometimes lead to the development or exacerbation of NMS, which can be difficult to manage. Another factor of interest is the use of non-steroidal anti-inflammatory drugs (NSAIDs) for managing pain in patients with PD. Recent studies have reported that NSAIDs may reduce the risk of PD in some individuals and could reduce CNS inflammation, which may be involved in some NMS [13–17].
Overall, more insight into the prescribing practices of anti-PD drugs and NSAIDs for PD in Japan is needed, including knowledge about changes in prescribing practices according to the progression of PD. Such data could be useful for optimizing the management of NMS to improve upon holistic approaches of care, which encompass all aspects of the life of PD patients.
The J-FIRST study, which started in 2014, was a 52-week observational study that was designed to gain a clearer picture surrounding NMS, motor symptoms, quality of life, and treatment practices in over 1000 Japanese patients with advanced PD across 35 study sites [18–21]. Of note, the study revealed marked differences in the patterns of NMS among Japanese patients, including sex-related differences in the prevalence and severity of NMS [18], as well as marked changes in NMS that were associated with changes in quality of life (assessed using the 8-item Parkinson’s Disease Questionnaire [PDQ-8]) over time [19]. Additionally, patient background characteristics were compared among patients divided into three groups based on the change in NMS (improved/unchanged/deteriorated) [19]. To better understand these earlier findings and to provide more insight into the management of Japanese patients with PD, we performed further analyses of the J-FIRST study to answer the following research questions:
- Do the prescriptions of anti-PD drugs and NSAIDs change over time in patients with PD in Japan? To our knowledge, this is the first study to examine the prescription practices for NSAIDs in Japan.
- How do the prescriptions for anti-PD drugs and NSAIDs change among Japanese patients stratified by whether their NMS improved, unchanged, or deteriorated based on their changes in Movement Disorder Society‒Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I scores?
- Do the prescriptions of major anti-PD drugs and NSAIDs vary among regions of Japan?
Methods
Ethics
The study was approved by the Ethics Review Committees at all participating sites. The study was conducted in compliance with the Ethical Guidelines for Epidemiological Research in the spirit of the Declaration of Helsinki. All patients provided written informed consent prior to participation. The study was registered on ClinicalTrials.gov (NCT02073981) and the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (umin.ac.jp/ctr/index-j.htm; UMIN000013161).
Study design
The design of the study has been reported in more detail [18, 19]. Between March 1, 2014 and January 31, 2015, the study enrolled patients with advanced-stage PD aged ≥20 years who were displaying wearing-off on levodopa-containing therapy and had ≥1 NMS assessed using MDS-UPDRS Part I. This study was exploratory in nature, and it was challenging to plan the sample size from a confirmatory perspective. As we previously described [18], we set the sample size at 1000 patients considering the feasibility of the study and the required number of patients to identify factors related to NMS. Overall, 996 patients satisfied the eligibility criteria and were included in the present analyses as the overall sample. Patients were enrolled across 35 sites distributed throughout Japan. These sites were broadly divided into East and West Japan.
This was an observational study of clinical practice with a 52-week follow-up in which all treatments were prescribed at the attending physician’s discretion. At baseline, the physicians collected data regarding patient characteristics, comorbid motor symptoms and NMS, MDS-UPDRS Parts I and IV (4.3), modified Hoehn and Yahr stage (mH&Y, ON and OFF states), and PDQ-8. At Weeks 0, 13, 26, 39, and 52, the participating physicians also collected data regarding the prescriptions for anti-PD drugs and NSAIDs with their doses (S1 Table), together with MDS-UPDRS Part I scores. The MDS-UPDRS Part I scores at Weeks 0, 13, 26, 39, and 52 were used to categorize patients according to whether the NMS status of PD improved, unchanged, or deteriorated using the group-based trajectory models described in the previous article [19].
Statistical analyses
In this study, we used the overall sample to determine the changes in prescription rates and doses over time for the anti-PD drugs and NSAIDs listed in S1 Table. These analyses were also repeated in patients divided into three groups according to the change in MDS-UPDRS Part I score (i.e., improved, unchanged, or deteriorated) [19] and in patients divided into two major geographical regions (East and West Japan). We used generalized linear models (GLM) for the analyses of prescription rates in the overall sample and in the patient subgroups (improved/unchanged/deteriorated and East/West Japan). The models of dosing in the overall sample were adjusted for age, sex, body mass index, duration of PD, age at PD onset, and mH&Y Score (ON). All these variables, except for body mass index, were used in the analysis by region. The results are presented as estimates ± standard error (SE). The estimates and SE for the prescription rates were originally calculated on a scale of 0–1 and converted into percentages on a scale of 0%–100% to aid interpretation. We determined P-values for the change from Week 0 to 52 in the analyses of the overall sample and for the analysis by the change in NMS status (i.e., improved/unchanged/deteriorated), but not for the analysis by region. All analyses were considered exploratory and P-values of <0.05 (two-sided) were considered significant without adjustment for multiple comparisons. SAS software (version 9.4; SAS Institute Inc., Cary, NC) was used for the analyses.
Results
Prescription status of the overall sample
As explained in a previous paper [19], 996 patients were enrolled and eligible for the analyses. There were 624 females (62.7%) and 372 males (37.3%), with a mean (standard deviation [SD]) age of 68.1 (8.8) years, mean (SD) PD duration of 10.9 (5.5) years, and mean (SD) age at PD onset of 58.1 (9.9) years. As expected from the eligibility criteria, the patients had advanced PD, with a mean (SD) number of comorbid NMS of 6.6 (2.5), a mean (SD) MDS-UPDRS Part I total score of 10.9 (5.4), and a mean (SD) MDS-UPDRS Part IV (4.3) score of 1.4 (0.7). According to the mH&Y scale, the ON state was classified as mild (0–2.5), moderate (3), and severe (4, 5) for 65.36%, 28.51%, and 5.92% of patients, respectively. The OFF state was classified as mild, moderate, and severe in 19.18%, 44.68%, and 35.84% of patients, respectively. The mean (SD) PDQ-8 total score at baseline was 7.3 (5.2). The mean (SD) dosage of levodopa-containing drugs was 436.4 (165.7) mg/day, and the mean (SD) levodopa-equivalent dose (LED) at baseline was 769.5 (339.0) mg/day.
The anti-PD drugs and NSAIDs prescribed to patients in the overall sample during the 52-week observational period are shown in Fig 1. Dopamine agonists were the most frequently prescribed drugs (range: 80.8% to 82.2% of patients) used in combination with levodopa-containing drugs throughout the observation period. Other commonly used drugs were entacapone (42.6% to 45.9%), zonisamide (34.9% to 37.5%), istradefylline (23.2% to 41.4%), selegiline (31.3% to 34.3%), and amantadine (26.3% to 27.2%). The least frequently used drugs were droxidopa (11.1% to 11.6%), anticholinergics (9.2% to 10.5%), and NSAIDs (2.4% to 3.2%). The prescription rate for istradefylline increased significantly whereas the prescription rate for selegiline decreased significantly (both: P < 0.05, GLM) between Weeks 0 and 52 (Fig 1). Additionally, the prescription rate increased significantly for rotigotine and decreased significantly for pramipexole (both: P < 0.05, GLM) (S1 Fig).
Values were calculated as estimates (0.0–1.0) ± standard error and converted to percentages (0%–100%). *P < 0.05 for Week 52 vs. Week 0 (generalized linear model). NSAIDs: non-steroidal anti-inflammatory drugs.
Regarding the daily doses of anti-PD drugs, Fig 2 shows there were significant increases from Week 0 to Week 52 in the doses of levodopa-containing drugs and the LED (both: P < 0.05, GLM). In particular, the dose of levodopa-containing drugs increased by 12.3 ± 5.8 mg/day (estimate ± SE) and LED increased by 49.0 ± 11.0 mg/day (estimate ± SE). Moreover, there were significant increases from Week 0 to Week 52 in the doses of rotigotine, entacapone, istradefylline and droxidopa, whereas there was a significant decrease in the dose of pergolide during this period (all: P < 0.05, GLM). The doses of other drugs remained stable.
(A) Levodopa-containing drugs. (B) Levodopa equivalent dose. (C) Pergolide. (D) Cabergoline. (E) Pramipexole. (F) Ropinirole. (G) Apomorphine. (H) Rotigotine. (I) Entacapone. (J) Selegiline. (K) Zonisamide. (L) Amantadine. (M) Istradefylline. (N) Droxidopa. Values are estimates ± standard error. The number of patients (%) prescribed each drug at Week 0 is indicated. *P < 0.05 for Week 52 vs. Week 0 (generalized linear model). LED: levodopa-equivalent dose.
Prescription status according to the change in NMS status during the observation period
Patients were divided into three groups based on the pattern of MDS-UPDRS Part I scores during the 52-week observation period: improved (N = 161), unchanged (N = 635), and deteriorated (N = 200) [19]. The baseline characteristics of these groups are presented in Table 1. Although no formal statistical comparisons were made, some differences in the baseline characteristics were apparent. In particular, the improved group had higher baseline MDS-UPDRS Part I and more patients with severe mH&Y scores for ON and OFF states, indicative of more severe disease at baseline.
There were statistically significant differences in the prescription rates of several drugs at Week 52 among the three groups (Fig 3). The deteriorated group had a higher prescription rate of entacapone than the improved (P = 0.0079, GLM) and unchanged (P = 0.0040, GLM) groups, and had a higher prescription rate of istradefylline than the unchanged group (P = 0.0110, GLM). By comparison, the improved group had a higher prescription rate of zonisamide than the unchanged group (P = 0.0366, GLM). We also examined the change in the prescription rate of NSAIDs. At Week 52, the improved group had a higher prescription rate of NSAIDs than the unchanged (P = 0.0070, GLM) and deteriorated (P = 0.0031, GLM) groups (Fig 3).
Prescription rates of antiparkinsonian drugs and non-steroidal anti-inflammatory drugs during the observation period in patients divided according to the pattern of change in non-motor symptoms: improved (A), unchanged (B), and deteriorated (C). Values are estimates ± standard error. Symbols indicate significance at a level of α = 0.05 (generalized linear model): *zonisamide—improved group vs. unchanged group; †NSAIDs—improved group vs. unchanged and deteriorated groups; ‡entacapone—deteriorated group vs. improved and unchanged groups; §istradefylline—deteriorated group vs. unchanged group. NSAIDs: non-steroidal anti-inflammatory drugs.
Regarding the changes in daily doses of drugs, we found significant increases from Week 0 to Week 52 in the dose of levodopa-containing drugs in the unchanged group and the LED in the improved and unchanged groups (all P < 0.05, GLM; Fig 4), but there were no statistically significant differences among the three groups at Week 52. The improved group had a higher prescribed daily dose of entacapone at Week 52 than the unchanged (P = 0.0014) and deteriorated (P = 0.0437) groups (S2 Fig).
Prescribed doses of levodopa-containing drugs (A) and the levodopa-equivalent dose (B) during the observation period for the improved, unchanged, and deteriorated groups. Values are estimates ± standard error. The number of patients (%) in each group is indicated. *P < 0.05 for Week 52 vs. Week 0 (generalized linear model). LED: levodopa-equivalent dose.
Prescription status according to region
Fig 5 depicts the prescription rates of anti-PD drugs and NSAIDs in West and East Japan separately. Some inconsistencies in the prescriptions of concomitant drugs between East and West Japan were apparent. Although there was no marked difference in the prescribed dose of levodopa-containing drugs between East and West Japan, the LED tended to be greater in East Japan (Fig 6).
Prescription rates for antiparkinsonian drugs and non-steroidal anti-inflammatory drugs during the observation period for West (A) and East (B) Japan. Values were calculated as estimates (0.0–1.0) and converted to percentages (0%–100%). NSAIDs: non-steroidal anti-inflammatory drugs.
Prescribed doses of levodopa-containing drugs (A) and the levodopa-equivalent dose (B) during the observation period for West and East Japan. Values are estimates ± standard error. LED: levodopa-equivalent dose.
Discussion
We investigated the treatment practices for advanced PD patients who were taking levodopa-containing drugs and displaying wearing-off, and enrolled in the observational J-FIRST study across 35 sites between February 2014 and December 2016. In this cohort of patients taking levodopa-containing drugs, dopamine agonists were the predominant combination treatment throughout the observation period, being prescribed to 80.8% to 82.2% of patients, whereas entacapone was the second-most frequent drug, being prescribed to 42.6% to 45.9% of patients. In the overall sample, it can be inferred that the prescription rates and doses of newer anti-PD drugs (e.g., rotigotine and istradefylline) increased during the observation period, whereas the prescription rates decreased for older classes of anti-PD drugs (e.g., pramipexole and selegiline). Rotigotine and istradefylline were launched in Japan in 2013, just prior to the start of the J-FIRST study, and the increase in the prescription rates and doses may be due to the expectations for these drugs. Rotigotine was launched earlier (2006 in the EU and 2007 in the USA), and some reports have examined its efficacy for NMS [22, 23]. Another possible explanation is that because rotigotine is a transdermal patch, its use is increasing especially among patients with dysphagia who find it difficult to swallow oral drugs. Rotigotine may also be prescribed to patients with gastrointestinal disorders that interfere with drug absorption. Istradefylline is a non-dopaminergic drug, and expectations for its effects on NMS may have been high, and it may have been prescribed to patients whose NMS had not improved sufficiently with dopaminergic drugs. Over time, physicians may have become more aware of the properties and clinical efficacy of the newer anti-PD drugs, and hence they may have become more willing to prescribe them at appropriate doses in clinical practice.
Examining the prescription trends in clinical trials conducted in other countries of advanced PD patients who were also taking levodopa-containing drugs, the dosage of levodopa-containing drugs at baseline ranged from 572 to 821 mg/day in earlier studies [24–27], as compared with 436.4 mg/day in the J-FIRST study. Differences were observed in the prescription rates at baseline in other countries (dopamine agonists, 57.1%–91.3%; monoamine oxidase B [MAO-B] inhibitor, 10.5%–21.8%; catechol-O-methyl transferase [COMT] inhibitor, 23.3%–50.3%; amantadine, 13.0%–26.1%; anticholinergics, 9.5%–39.2%) as compared to the J-FIRST study (dopamine agonists, 80.9%; MAO-B inhibitor, 33.5%; COMT inhibitor, 43.6%; amantadine, 26.3%; anticholinergics, 10.3%). These values in J-FIRST are also very similar to those of other recent studies in Japan (dose of levodopa-containing drugs, 399.3–446.5 mg/day; dopamine agonists, 72.1%–95.7%; MAO-B inhibitor, 47.1%–55.5%; COMT inhibitor, 12.7%–45.6%; amantadine, 16.3%–38.1%; anticholinergics, 5.1%–19.5%) [28–31]. Although the data should not be directly compared among studies, the dose of levodopa-containing drugs tended to be lower in Japan than in other countries (as described above and in [32]), whereas the prescription rates of other drugs tended to be similar or slightly higher in Japan than in other countries. These differences in prescription trends suggest that Japanese physicians are attempting to control the symptoms of advanced PD by combining levodopa-containing drugs with other anti-PD drugs, without increasing the dose of levodopa-containing drugs.
In our study, the unchanged group showed a significant change in the dose of levodopa-containing drugs, and the improved and unchanged groups showed significant changes in LED. These changes may have helped prevent/delay disease progression and/or led to improvements in NMS in these patients, especially when coupled with the increases in the doses and prescription rate of other anti-PD drugs and NSAIDs. The improved or deteriorated groups showed a tendency for higher prescriptions of some anti-PD drugs than the other group(s). A reason for this may be that these drugs may have been added to existing therapy due to worsening symptoms during the observation period in the deteriorated group, or contributed to the improvement in symptoms in the improved group. However, there was no clear evidence as to whether the symptoms improved/deteriorated due to the addition of these drugs. Regarding NSAIDs, some pharmacoepidemiologic reports have suggested that they can suppress the onset or progression of PD [13–15]. An earlier clinical study examined the relationship between NMS and inflammatory cytokines, and the authors suggested that NSAIDs may have an effect on NMS [33]. Although this could not be investigated in the present study with a 52-week observation, the improved group was prescribed NSAIDs more frequently, which may have contributed to the improvement of NMS. Therefore, prescribing NSAIDs may be a good adjunct to anti-PD drugs, provided that they are used with appropriate consideration for the potential side effects of NSAIDs, such as peptic ulcers.
The LED tended to be greater in East Japan than in West Japan. A reason for this may be that the prescription rate of concomitant drugs, other than levodopa-containing drugs, differed between East and West Japan. Unfortunately, due to the nature of the study, the reasons for these inconsistencies cannot be ascertained from the available data. Further studies may be useful to help understand the factors underlying the geographical inconsistencies of anti-PD drug and NSAID prescriptions in Japan.
Limitations
There are limitations of the J-FIRST study that should be mentioned, beyond those described in the prior articles [18–21]. In particular, it was not possible to assess whether the changes in treatments were done in order to improve the patient’s NMS status or whether they were a response to clinical factors (e.g., tolerability or as a consequence of changes in other therapies). Motor deterioration is often a cause of therapy adjustments in PD. However, because the UPDRS III score was not measured in this study, we could not examine the relationship between motor deterioration and therapy adjustments. Further, it was not possible to determine the factors that may contribute to the geographical differences in anti-PD drug and NSAID prescriptions between East and West Japan. Additionally, the patients were enrolled between March 2014 and January 2015, predating the approval of new MAO-B inhibitors and a new COMT inhibitor. Thus, the results may not reflect current treatment practices in Japan.
Conclusions
In conclusion, the results of this study have revealed significant changes in the prescriptions and doses of selected anti-PD drugs and NSAIDs for advanced PD patients with ≥1 NMS in Japan. Japanese physicians tended to increase the number of prescriptions and doses of newer drugs during the observation period. We also observed differences in anti-PD drug and NSAID prescriptions among subgroups of patients divided by their NMS status (improved/unchanged/deteriorated) and geographic region. Further studies might be useful to better understand these findings and evaluate their clinical relevance.
Supporting information
S1 Fig.
Prescription rates of rotigotine (A) and pramipexole (B) during the observation period for the overall sample. Values were calculated as estimates (0.0–1.0) ± standard error and converted to percentages (0%–100%). *P < 0.05 for Week 52 vs. Week 0 (generalized linear model).
https://doi.org/10.1371/journal.pone.0309297.s003
(PDF)
S2 Fig.
Prescribed doses of antiparkinsonian drugs during the observation period for the improved, unchanged, and deteriorated groups of patients: (A) pergolide, (B) cabergoline, (C) pramipexole, (D) ropinirole, (E) apomorphine, (F) rotigotine, (G) entacapone, (H) selegiline, (I) zonisamide, (J) amantadine, (K) istradefylline, and (L) droxidopa. Values are estimates ± standard error. The number of patients (%) prescribed each drug at baseline is indicated. *P < 0.05 for the improved group vs. the unchanged and deteriorated groups at Week 52 (generalized linear model).
https://doi.org/10.1371/journal.pone.0309297.s004
(PDF)
Acknowledgments
The authors acknowledge A2 Healthcare, Japan, for their role in data management. Editorial support was provided by Nicholas D. Smith, PhD (EMC K.K.).
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