Pain represents one of the most prevalent non-motor symptoms in patients with idiopathic Parkinson’s disease (PD). Remarkably, its onset can precede the formal diagnosis of PD, underscoring its significance as an early symptom [1,2]. Despite its prevalance, pain in PD is often remains underdiagnosed and undertreated, significantly impacting the quality of life of patients [3,4]. Various factors contribute to pain in PD, including musculoskeletal problems, dystonia, akathisia, rigidity, and neuropathic pain [5]. Ford’s classification categorizes pain in PD into five distinct groups: musculoskeletal pain (MSP), radicular/neuropathic pain (RNP), dystonia-related pain (DRP), central parkinsonian pain (CPP), and akathitic discomfort [6].

Neuropathic pain is characterized by pain, such as burning, tingling, stabbing, numbness, or electric-shock-like pain often together with hyperalgesia and allodynia. It is caused by a lesion in the somatosensory nervous system [7]. Neuropathic pain in PD, as per Ford's classification, is further divided into two subgroups: RNP and CPP [6]. RNP typically arises along specific peripheral nerve or nerve root innervation areas and is attributed to damage from postural deformity and dyskinesia [8]. In contrast, CPP lacks clear localization and is characterized by neuropathic features, believed to stem from alterations in central pain pathways and pain processing in PD [9–11].

Given the multifaceted nature of pain in PD, this study aims to provide a comprehensive evaluation of its prevalence within the patient cohort. Additionally, the authors endeavored to identify and analyze factors associated with pain in PD, with particular focus on discerning disparities between neuropathic pain and other pain types.

1. Patients selection and clinical assessment

Patients diagnosed with idiopathic PD, who underwent examination at the Movement Disorders Outpatient Clinic in the Department of Neurology, Sisli Hamidiye Etfal Training and Research Hospital between September 2023 and January 2024, were prospectively enrolled in the study. All participants provided informent consent. The study protocol received approval from the local ethical committee (approval date and number: 29.08.2023-2428), and all patients underwent assessment by a movement disorder specialist. Patients diagnosed with idiopathic PD were included in the study. Exclusion criteria encompassed parkinsonism arising from causes other than idiopathic PD, conditions predisposing to polyneuropathy such as diabetes, established polyneuropathy, use of medications potentially causing polyneuropathy, treatment with levodopa-carbidopa intestinal gel or deep brain stimulation (DBS), malignancy, dementia, and lack of willingness to participate in the study. Conditions such as disc herniation and spinal stenosis were excluded based on clinical evaluations, patient history, and prior spinal imaging when available.

All assessments were conducted with patients in the 'on' state. The Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) was completed for each patient during the examinations [12]. Disease stages were determined according to the Hoehn and Yahr (H&Y) Scale [13]. Additionally, patient demographics, PD duration, age at disease onset, presence of sleep disorders, restless leg syndrome (RLS), and other comorbidities were documented.

2. Pain assessment

Pain features, including severity, frequency, duration, and affected body parts, were assessed using a pain-assessment questionnaire, with severity quantified using the visual analog scale [14]. Neuropathic pain was identified using the self-administered Leeds Assessment of Neuropathic Symptoms and Signs scale [15]. Pain types were categorized according to Ford's classification as follows: MSP, RNP, DRP, and CPP [6]. Akathitic discomfort was not separately assessed in this study due to its low prevalence among its cohort.

3. Depression, anxiety, and health-related quality of life assessments

Depression and anxiety levels were assessed using the Patient Depression Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) scale, respectively [16,17]. Health-related quality of life was evaluated using the 3-level version of EQ-5D (EQ-5D-3L) by the EuroQol Group [18].

4. Statistical analyses

First, patients were categorized into two groups: those with pain and those without pain. The groups were compared regarding age, sex, age at disease onset, PD duration, medications, MDS-UPDRS III, EQ-5D-3L, H&Y stage, depression, anxiety, RLS, rapid eye movement sleep behaviour disorder (RBD), and insomnia. Then, patients with pain were categorised into two groups acoording to their pain types: neuropathic pain and others. The same comparisons were conducted between these two groups.

All analyses were performed using the R statistical language (R Core Team, 2024). A confidence level of 0.95 was considered statistically significant. The distribution of the data was assessed using the Kolmogorov–Smirnov test, skewness, and kurtosis values. As none of the variables followed a normal distribution, descriptive statistics such as median, interquartile range (IQR), and absolute frequency were employed. Mann–Whitney U-test, Chi-squared test, logistic regression, and receiver operating characteristic (ROC) analysis were utilized to explore the relationship between variables and evaluate predictive models.

1. Clinical and demographic findings

During the study period, a total of 109 patients with PD were examined. Sixteen patients were excluded due to various reasons: 11 with diabetes mellitus, 2 with DBS, 2 with dementia, and one with chronic renal failure. The final analysis included 93 patients, comprising 34 females and 59 males, with a median age of 66 years (IQR: 17). The median duration of PD was 5 years (IQR: 5), with a median age at PD onset of 59 (IQR: 16). The median MDS-UPDRS III score was 16 (IQR: 12). Nine patients reported insomnia (9.6%), 10 (10.7%) had RLS, and 17 (18.2%) had RBD. The most common medications used were levodopa with benserazide (59 patients), rasagiline (51 patients), dopamine agonists (48 patients), levodopa with carbidopa and entacapone (25 patients), levodopa with carbidopa (24 patients), amantadine (10 patients), and aphomorphine (3 patients).

2. Types of pain

Among the 93 patients, 75 reported pain (80.6%). There were 40 patients (53.3%) with MSP, 27 patients (36%) with RNP, 15 patients (20%) with DRP, and 10 patients (13.3%) with CPP. Seventeen of them (22.6%) reported a combination of different pain types. Within the group reporting a combination of different pain types, 9 had both RNP and MSP, 5 had both CPP and MSP, and 3 had both DRP and MSP. Pain was located in the legs in 27 patients, in the lower back in 21, in the arms is 16, in the feet in 13, in the hands in 10, in the upper back in 9, in the shoulders in 6, in the knee in 6, generalised in 5, and in the buttocks in 4. Some patients experienced pain in more than one region of the body.

3. Findings of questionnaires

The median EQ-5D-3L scale score was 8 (IQR: 4), with a median self-reported health condition in EQ-5D-3L scale of 70% (IQR: 20%). The median PHQ-9 and GAD-7 scale scores were 5 (IQR: 8) and 4 (IQR: 8), respectively.

4. Pain-related factors

There were no statistically significant differences regarding age, sex, age at disease onset, PD duration, medications, H&Y stage, MDS-UPDRS III, GAD-7, and PHQ-9 scores, RLS, RBD, and insomnia between patients with pain and those without pain (P > 0.05) (Table 1). The univariate analysis revealed that higher EQ-5D-3L scores were related to a higher likelihood of having pain. Logistic regression analysis also revealed an association between pain in PD patients and EQ-5D-3L score (P = 0.019; Fig. 1). Specifically, a one-point increase in EQ-5D-3L score was associated with an approximately 86% increase in the odds of experiencing any type of pain.

Table 1 Differencies between patients with pain and patients without pain

Variable	Patients with pain (n = 75)	Patients without pain (n = 18)	P value
Age (yr)	64 (17)	69.5 (8.5)	0.744
Sex			0.544
Female	28 (37.3)	5 (27.8)
Male	47 (62.7)	13 (72.2)
Age at disease onset (yr)	58 (15.5)	64 (12)	0.125
Disease duration (yr)	5 (5.5)	3.5 (2.75)	0.744
MDS-UPDRS III score	18 (15)	13 (3)	0.695
Hoehn and Yahr Stage	2 (1)	1 (1)	0.245
GAD-7 scale score	5 (9)	3 (4.75)	0.460
PHQ-9 scale score	7 (9)	3 (5)	0.078
EQ-5D-3L questionnaire score	8 (3)	6 (2)	0.019
Insomnia	10 (13.3)	0 (0)	0.270
Rem sleep behavior disorder	18 (24.0)	8 (44.4)	0.302
Restless leg syndrome	10 (13.3)	4 (22.2)	0.899

Data are presented as median (interquartile range) for continuous variables and as number (%) for categorical variables.

MDS-UPDRS III: The Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part III, GAD-7: General Anxiety Disorder-7 scale, PHQ-9: Patient Depression Questionnaire-9 scale, EQ-5D-3L: 3-level version of EQ-5D (EQ-5D-3L) by the EuroQol Group.

Figure 1. Comparison of EQ-5D-3L scores between Parkinson’s disease patients with and without pain. EQ-5D-3L: 3-level version of EQ-5D (EQ-5D-3L) by the EuroQol Group.

When differences between patients with neuropathic pain (RNP + CPP) and patients with other pain types were analyzed, there were no statistically significant differences regarding age, sex, age at disease onset, medications, H&Y stage, MDS-UPDRS III, EQ-5D-3L, PHQ-9 scores, RLS, RBD, and insomnia (P > 0.05) (Table 2). Within the group experiencing pain, duration of PD was associated with neuropathic pain compared to other types of pain (P = 0.003). Specifically, a one-year increase in PD duration was associated with approximately a 27% increase in the odds of experiencing neuropathic pain. The authors evaluated the performance of the logistic regression models for predicting neuropathic pain using PD duration by utilizing an ROC curve. The area under curve was 0.71 (Fig. 2), suggesting that PD duration is a reasonably effective predictor of neuropathic pain in PD patients.

Table 2 Differencies between patients with neuropathic pain and patients with other types of pain

Variable	Patients with neuropathic pain (n = 38)	Patients with other types of pain (n = 37)	P value
Age (yr)	64 (9.5)	62 (17)	0.885
Sex			0.391
Female	15 (39.5)	14 (37.8)
Male	23 (60.5)	23 (62.2)
Age at disease onset (yr)	56 (14)	58 (16)	0.135
Disease duration (yr)	5 (6.75)	4 (4)	0.003
MDS-UPDRS III score	18.5 (10.75)	15 (16)	0.898
Hoehn and Yahr Scale	2 (1)	2 (1)	0.758
GAD-7 scale score	6 (7.75)	3 (9)	0.595
PHQ-9 scale score	7.5 (9.5)	5 (9)	0.071
EQ-5D-3L questionnaire score	8 (4)	8 (4)	0.430
Insomnia	5 (13.2)	4 (10.8)	0.791
Rem sleep behavior disorder	9 (23.7)	8 (21.6)	0.660
Restless leg syndrome	5 (13.2)	5 (13.5)	0.814

Data are presented as median (interquartile range) for continuous variables and as number (%) for categorical variables.

MDS-UPDRS III: The Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part III, GAD-7: General Anxiety Disorder-7 scale, PHQ-9: Patient Depression Questionnaire-9 scale, EQ-5D-3L: 3-level version of EQ-5D (EQ-5D-3L) by the EuroQol Group.

Figure 2. Receiver operating characteristic (ROC) curve for predicting neuropathic pain based on Parkinson’s disease (PD) duration. AUC: The area under curve.

MSP was reported by 40 patients (20 female, 20 male), RNP by 27 patients (10 female, 17 male), DRP by 15 patients (2 female, 13 male), and CPP by 10 patients (4 female, 6 male). Among the 34 female patients, 20 (58.8%) had MSP. When analyzing the four pain types separately according to sex differences, MSP was found to be more common in females (P = 0.012; Fig. 3). GAD-7 scores correlated only with the presence of CPP, indicating that anxiety was more prevalent in patients with CPP (P = 0.008; Fig. 4). DRP was more common in patients with higher MDS-UPDRS III scores (P = 0.039; Fig. 5), with a one-point increase in UPDRS III scores associated with a 109% increase in the odds of having DRP. Additionally, RNP was less common in patients taking amantadine (P = 0.043). There were no statistically significant differences regarding age, age at disease onset, H&Y stage, PHQ-9 scores, RLS, RBD, and insomnia among the four different pain types (P > 0.05).

Figure 3. Distribution of pain types according to sex. RNP: radicular/neuropathic pain, MSP: musculoskeletal pain, DRP: dystonia-related pain, CPP: central parkinsonian pain.

Figure 4. Distribution of GAD-7 scores across different pain types. GAD-7: General Anxiety Disorder-7 scale, RNP: radicular/neuropathic pain, MSP: musculoskeletal pain, DRP: dystonia-related pain, CPP: central parkinsonian pain.

Figure 5. Distribution of MDS-UPDRS III scores across different pain types. MDS-UPDRS III: The Movement Disorders Society-Unified Parkinson’s Disease Rating Scale part III, RNP: radicular/neuropathic pain, MSP: musculoskeletal pain, DRP: dystonia-related pain, CPP: central parkinsonian pain.

The most important findings of this study were as follows: higher EQ-5D-3L scores were related to a higher likelihood of having pain, MSP was more common in females, anxiety was more prevalent in patients with CPP, DRP was more common in patients with high MDS-UPDRS III scores, RNP was less common in patients taking amantadine, and longer PD duration was linked to the presence of neuropathic pain.

Consistent with previous literature [9,19–21], these findings underscore the high prevalence of pain in PD, with 80.6% of the patient cohort reporting pain. Notably, the frequency of RNP and CPP observed in the present study aligns with previous reports, further corroborating their significance in the PD pain spectrum [8–10,19].

Interestingly, no significant differences were found in demographic and clinical characteristics between PD patients with and without pain. This suggests that pain in PD may not be influenced by factors such as age, sex, disease duration, or severity. However, the logistic regression analysis revealed a notable association between pain and lower health-related quality of life, as indicated by EQ-5D-3L scores in line with the literature [22].

While most of the demographic and clinical characteristics did not significantly differ between patients with neuropathic pain and other pain types, PD duration emerged as a significant predictor of neuropathic pain. This underscores the progressive nature of neuropathic pain in PD, with longer disease duration associated with an increased likelihood of experiencing such pain. While the exact mechanisms underlying this association warrant further investigation, the authors’ findings suggest that disease progression may contribute to the development or exacerbation of neuropathic pain in PD patients. This aligns with previous research highlighting the progressive nature of neuropathic pain in neurodegenerative disorders [23].

Additionally, the findings suggest potential sex differences in pain manifestation, with MSP being more prevalent in females. This finding is consistent with the existing literature suggesting sex-specific variations in pain sensitivity and perception [19,20,24]. Ovarian hormones, especially estrogens, have an important role in the pain pathway, including modulating signal transmission of pain perception, the transmission of painful stimuli through the spinal cord, and modulating pain perception in the pain-related areas such as the thalamus, periaqueductal grey matter, and amygdala [25]. Additionally, it has been shown that MSP is more common in elderly women, emphasizing the effect of menopause, and it has been speculated that this is related to low estrogen levels [26]. The observed differences underscore the importance of considering sex as a potential determinant in pain assessment and management strategies for PD patients.

Moreover, anxiety was found to be more common in patients with CPP, emphasizing the intricate interplay between pain and psychological factors in PD. Previous studies have suggested an intricate relationship between pain and psychological comorbidities, with anxiety often exacerbating pain symptoms [27–29]. The present study’s findings support this notion, with anxiety being more prevalent among patients experiencing CPP, implying a potential interplay between psychological distress and certain pain types in PD.

Despite the small number of patients, the authors’ findings indicate that RNP was less common in those taking amantadine. Previous studies have demonstrated that glutamate plays an important role in CPP [30] and amantadine can reduce pain by modulating pain perception and decreasing sensitization [31]. These results are promising and suggest a potential therapeutic role for amantadine in pain management, although further research with larger patient cohorts is necessary to confirm these findings and fully understand the underlying mechanisms.

There are some limitations of this study. First, pain is a subjective symptom and based-on patients’ self reporting. Second, it is a cross-sectional study and has no longitudinal follow-up period. Additionally, despite it being beyond the scope of this study, the authors did not perform any radiological imaging or electromyography to evaluate patients who reported neuropathic pain. Future studies should consider incorporating objective measures, such as electromyography, to enhance the robustness of the findings.

In conclusion, this study highlights the high prevalence of pain in PD, affecting 80.6% of patients, with significant associations between pain and lower health-related quality of life. The authors found that RNP is linked to longer disease duration, while MSP is more common in females, suggesting sex-specific variations in pain sensitivity. Anxiety was notably more prevalent in patients with CPP, underscoring the intricate interplay between pain and psychological factors. Additionally, this study’s findings suggest a potential therapeutic role for amantadine in reducing RNP. These results emphasize the need for tailored pain management strategies in PD.

The datasets supporting the findings of this study are available from the corresponding author upon reasonable request.

No potential conflict of interest relevant to this article was reported.

No funding to declare.

Ceren Alis: Conceptualization & Methodology, Data curation, Formal analysis and investigation, Writinig-original draft; Derya Selcuk Demirelli: Conceptualization & Methodology, Data curation, Formal analysis and investigation; Elvin Ay: Conceptualization & Methodology, Data curation, Formal analysis and investigation, Writinig-original draft; Gencer Genc: Conceptualization & Methodology, Data curation, Formal analysis and investigation, Writing-review&editing, Supervision.

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