Effects of safinamide on pain in patients with fluctuating Parkinson's disease

Abstract Background Non‐motor symptoms (NMS) are integral to Parkinson's Disease (PD) and management remains a challenge. Safinamide is a novel molecule in relation to addressing NMS due to its multifocal mechanism of action with both dopaminergic and non‐dopaminergic properties. Objective To investigate the efficacy of safinamide on NMS and its burden in PD patients with motor fluctuations after 6 months of treatment. Methods This observational, multicenter, open‐label, pilot study assessed a wide range of NMS using the following rating scales, NMSS (non‐motor symptom scale), KPPS (King's PD pain scale), HADS (hospital anxiety and depression scale), PDQ‐8 (Parkinson's disease quality of life questionnaire), and PDSS‐2 (Parkinson's disease sleep scale), EuroQol‐5D 3 level version (EQ‐5D‐3L), CGI‐I (clinical global impression of improvement), and PGI‐C (patient global impression of change). Motor examination using UPDRS part III (Unified Parkinson's disease rating scale, motor examination), UPDRS IV (complications of therapy) and Hoehn and Yahr staging were also obtained. Results 27 patients were included in the analysis and were evaluated at baseline and ≥ 6 months after safinamide treatment. 26 patients had a daily maintenance dose of 100 mg and 1 patient a daily dose of 50 mg. Significant improvements in UPDRS IV, KPPS item 5 (region‐specific “off” dystonia), KPPS domain 3 (items 4–6, fluctuation related pain) and KPPS total score were observed after treatment with safinamide, while maintaining stable dopaminergic medication. No statistically significant differences were found in NMSS, HADS, PDSS‐2, EQ‐5D‐3L, and PDQ‐8 after treatment. Conclusions Our results suggest that safinamide may have a beneficial effect on pain, a key unmet need in fluctuating PD patients.


INTRODUCTION
The classic findings of Parkinson's disease (PD) are motor and resultant from dopamine deficiency within the basal ganglia (Kalia and Lang, 2015), while non-motor symptoms (NMS) have a more complex pathophysiology and can range from the prodromal to the palliative stage.
It is common for patients with advanced PD to experience a number of NMS (neuropsychiatric problems, sleep disorders, pain, autonomic symptoms including gastrointestinal and urogenital etc.), while some NMS already appear in the preclinical phase of the disease, such as, anosmia and rapid eye movement sleep behavior disorder (RBD) (Chaudhuri and Odin, 2010;Pont-Sunyer et al., 2015;Poewe, 2008;Gallagher et al., 2010;Maass and Reichmann, 2013). The pathophysiology of NMS is multifactorial and it is believed that dysfunction of both dopaminergic and non-dopaminergic systems contribute to their development. Outside of the nigrostriatal pathway, α-synuclein can have a diverse neuroanatomical distribution that differs from patient to patient, which likely accounts for different non-motor manifestations in PD patients (Chaudhuri and Schapira, 2009;Lang and Obeso, 2004;Barone, 2010;Adler and Beach, 2016).
NMS have a significant cumulative effect on patients' daily activities and quality of life (Kadastik-Eerme et al., 2016). Studies have shown that NMS, as a whole, may have a greater impact on the patients' quality of life than motor symptoms and that the NMS progression contributes to further decline of the quality of life in PD patients (Gallagher et al., 2010;Martinez-Martin et al., 2011).

MAO-B inhibitors prevent the breakdown of dopamine and stabilize
dopamine concentrations in the synaptic cleft, prolonging the effects of dopamine (Szökő et al., 2018). Due to their mechanism of action they offer a limited amelioration of impaired motor behavior and wearingoff phenomena in PD patients (Riederer and Müller, 2018). They are indicated for initiation of treatment in patients with mild PD symptoms before the initiation of levodopa, or mainly as an add-on treatment in PD patients with fluctuations at a later stage (Overview, 2017 (Blair and Dhillon, 2017). It has a unique mechanism of action that includes both dopaminergic and non-dopaminergic properties, as it leads to an inhibition of glutamate release by modulation of calcium-and sodium ion channels (Caccia et al., 2006;Müller and Foley, 2017). Numerous studies have shown that safinamide has a positive effect on motor symptom control, ON-time and fluctuations in both early and advanced PD, having a dopamine-sparing effect, as well as, being generally well tolerated (Cattaneo et al., 2016;Stocchi et al., 2012;Barone et al., 2013;Hattori et al., 2020). Safinamide's compound dopaminergic and non-dopaminergic properties make it an interesting agent in the field of NMS and neurodegeneration in PD (Pisanò et al., 2020;Maiti et al., 2017;Zhang et al., 2016;Sadeghian et al., 2016) and especially pain, that has previ-ously been associated with high glutamatergic activity (Watson, 2016;Bleakman et al., 2006;Phillips and Clauw, 2011

Study design
The study is a collaboration between Skane University Hospital in

Patients
Patients were included according to the following inclusion criteria: an age of 30 to 90 years; a diagnosis of idiopathic PD; a Hoehn and Yahr stage of I-IV during "off" phase; motor fluctuations, with >1.5 h "off" time during the day; and have been receiving treatment with a stable dose of levodopa for at least 4 weeks. The exclusion criteria were the same as in the safinamide SETTLE study . Safinamide was initiated at a 50 mg dose once daily and was up-titrated to a maintenance dose of 100 mg once daily for 26 of the 27 patients, while one patient chose to remain on a maintenance dose of 50 mg once daily throughout the study.
We recruited 38 patients; 5 patients were screening failures and 4 dropouts (early discontinuation due to loss of interest in completing the study/ no significant subjective motor improvement in comparison to rasagiline/ medication cost), while 2 patients were excluded from the statistical analysis because of changes in their anti-parkinsonian F I G U R E 1 Patient flow chart medications during the study. The remaining 27 patients were included in the final analysis ( Figure 1).

Assessments
The patients were evaluated using well-known, validated and broadly  (Guy, 1976). UPDRS part III (unified Parkinson's disease rating scale, motor examination), UPDRS IV (complications of therapy) (Fahn, 1987) and Hoehn and Yahr staging were also obtained.
Motor examination UPDRS part III and Hoehn and Yahr staging were performed during "on" phase, as recommended by the MDS taskforce.
Pain was assessed prior to and while on safinamide treatment using the King's PD pain scale (KPPS), a 14-item, PD-specific pain scale. Each item is scored by severity (0-3) multiplied by frequency (0-4), resulting in a sub-score of 0 to 12. There is a total possible score range from 0 to 168, and pain is classified into 7 different domains (Domain 1: Item 1, Domain 2: Item 2-3, Domain 3: Item 4-6, Domain 4: Item 7-8, Domain 5: 9-11, Domain 6: Item 12-13, Domain 7: Item 14) (Chaudhuri et al., 2015). The English version of KPPS was used for patient evaluation in both Germany and Sweden. as well as in sub-total and total scores. Paired samples t-test was used for data with normal distribution. The significance level used was p <

Statistical analysis
.05. The correlations between the baseline and follow-up differences in KPPS scores and UPDRS item 39 were calculated using the Spearman's rank order correlation coefficient. The concordance between the global impression of change from baseline to follow-up by patients and clinicians (PGI-C and CGI-C) was tested by means of percentage of agreement and weighted kappa with quadratic weights.

Ethics
The study was approved by the Swedish Ethical Review Authority and the Ethical Committee of Dresden, Germany. All patients signed an informed consent form and the study was conducted according to good clinical practice rules and to the Declaration of Helsinki.

RESULTS
Patients' demographic and clinical characteristics are summarized in Table 1.
The majority of the patients were male (22; 81%) and the mean age of the patients was 65 years. The PD duration was calculated with PD  Table 2.

F I G U R E 3
Changes in KPPS items, evaluated before and after ≥ 6 months of treatment with safinamide. X axis represents the different KPPS items/questions, clustered by time before and after treatment and Y axis the mean score of each KPPS item. Error bars represent 95% confidence interval PGI-C and CGI-C scales showed a very strong agreement between the patients' and the clinicians' global impression with a high kappa coefficient value, Kappa (95% CI) = 0.87 (0.73 -0.93). 10 patients improved at follow-up according to both PGI and CGI, while 5 patients had worse scores in both scales at follow-up. No change was noticed in 7 patients (both scales) and the rest of the cases showed a discrepancy between clinician-patient rating (PGI-CGI).  (Liguori et al., 2018), while in our study, we could only detect a nonsignificant reduction in the total PDSS-2 score. This finding could be attributed to the fact that the previously mentioned study included patients with a higher baseline PDSS-2 score than in our study (20.1 vs.

DISCUSSION
14.8), the difference in patient sample size (47 vs. 27) and the different study designs.
Post-hoc analyses from previous studies have shown positive effects of safinamide on mood and emotional well-being , as well as improvements in PD quality of life questionnaire (PDQ-39) questions related to pain, and a reduction of pain medications Cattaneo et al., 2018). A recent, prospective, observational study with 13 patients that focused on safinamide and pain also indicates a positive effect after 12 weeks of treatment (Geroin et al., 2020).
The results of our study also suggest a positive effect of safinamide in pain in PD patients, as has been reported in the studies mentioned above Geroin et al., 2020). In the 2 post-hoc analyses Cattaneo et al., 2018) at 6 months and 2 years after safinamide treatment respectively, the investigators observed a 24% and 26% reduction of pain medications, which aligns well with the 31% reduction in KPPS total score we found at F I G U R E 4 Changes in KPPS domains and total, before and after ≥ 6 months of treatment with safinamide. X axis represents the different KPPS items/questions, clustered by time before and after treatment and Y axis the mean score of each KPPS item. Error bars represent 95% confidence interval. Domain 1: Musculoskeletal pain, 2: Chronic pain, 3: Fluctuation-related pain, 4: Nocturnal pain, 5: Orofacial pain, 6: Discolouration; Oedema/Swelling, 7: Radicular pain 6 months in our cohort. The recent Italian study on safinamide and pain (Geroin et al., 2020) found an even more profound reduction in KPPS total score (approx. 50%), but had a shorter follow-up at 12 weeks and included patients with much higher pain burden (more than double KPPS total score at baseline) in comparison to our patient cohort.
In our patient group we were also able to show a significant improvement in the total KPPS score, as well as in the item 5, related to regionspecific "off" dystonia. KPPS Domain 3 (items 4-6, fluctuation related pain) was also significantly improved, with items 4 and 6 showing an improvement, though not statistically significant as separate items.
Our results indicate a low correlation of the improvement observed in KPPS item 5, KPPS domain 3, and KPPS total score and the changes in UPDRS item 39. This could suggest that pain improvement may not exclusively arise due to secondary reduction of motor fluctuation but can perhaps be attributed to safinamide's double (dopaminergic and anti-glutamatergic) mechanism of action. It should be kept in mind though that, probably due to the relatively small sample size, the Spearman's correlations did not reach statistical significance at the 0.05 level in our analysis. In order to prove this statement, further studies with a design that includes control groups (e.g. a PD group initiating safinamide with a comparable dose increment of dopaminergic medication or a control group treated with selegiline or rasagiline) are needed.
UPDRS part IV total score was also significantly reduced, with improvement (not statistically significant separately) noticed in all three parts of UPDRS IV (mainly Part A-fluctuations and Part Cother complications). While the UPDRS part III did not change significantly from baseline to follow up, this could be regarded in a positive light as the PD motor symptoms tend to deteriorate linearly as PD progresses (Holden et al., 2018). It should also be noted that while the UPDRS III assessments were performed in "on," they were not obtained at the same timepoints at baseline and follow-up.
We were not able to detect any other significant positive effects on NMS with the other scales used in the study. Total NMSS score showed only a trend of improvement, which however did not reach statistical significance and no changes could be detected in the patients' quality of life or general health status (as measured by PDQ-39 and EQ-5D-3L).
The main limitations of this study are the lack of blinding and ran- The main strengths of the study are the utilization of validated, wellknown clinical scales and measurements, its prospective nature and a patient group that was able in an observational setting to retain a stable antiparkinsonian treatment during the study. Furthermore, all evaluations were performed by the same clinician in each participating center at both visits, thus avoiding the issue of inter-rater variability.

CONCLUSION
Safinamide is an interesting agent for the treatment of PD and NMS due to its dopaminergic and non-dopaminergic mechanism of action.
Our study suggests that it seems to have a beneficial effect on pain, mainly fluctuation-related pain. Randomized trials with bigger patient populations as well as post marketing surveillance based studies are needed to confirm the effect of safinamide on different NMS, for example, pain, or detect other possible effects.

ACKNOWLEDGEMENTS
The authors would like to thank research nurse Gunilla Thorneman for her work throughout the study and Ms. Juliet Staunton for the editorial support. Reichmann Heinz has received compensation from Zambon for lectures and advisory board meetings.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2336