The Clinical Profile of Pain as a Non-motor Symptom in Parkinson’s Disease: A South Indian Experience

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide after Alzheimer’s disease.^[1] In recent times, non-motor symptoms (NMS) of PD have received global attention.^[2] The reported prevalence of PD-related pain varies in different studies.^[3-15] Patients who report pain symptoms were also significantly more likely to report depression and reduced quality of life.^[16] Most PD-related pain is secondary to motor disability (e.g., musculoskeletal and dystonic pain), however as many as 40% of patients with PD also experience primary pain in the early stages of PD, before motor symptoms become prominent.^[17] Recent studies suggest that pain may be the phenotypic hallmark of the “Park-Pain non-motor endophenotype”, raising the possibility that pain identifies a specific subgroup of patients who require specific and personalised therapeutic approaches.^[18]

Traditionally, pain in PD is classified into five domains: musculoskeletal, radicular/neuropathic, dystonia-related, akathitic and central pain, of which the most common are musculoskeletal and dystonic pain. Central PD pain is less common.^[19] Attempts to characterise and assess the severity of pain in PD have been made by several authors using different scales. In recent times, the Movement Disorders Society (MDS) has accepted the King’s Parkinson’s disease pain scale (KPPS) for characterising pain in PD. Indian research on pain contains only two studies from specific centres that have used the KPPS. This study intends to analyse the clinical profile of pain as a NMS in a South Indian population with PD using the KPPS.

MATERIAL AND METHODS

This study was conducted over a duration of 1 year in the Department of Neurology of a tertiary care hospital in Mangaluru, India. The primary objective of this study was to characterise the clinical profile of pain in patients with PD. The secondary objective was to study the severity of pain in patients with PD and to ascertain whether it correlates.

RESULTS

Nonmotor symptoms

The mean NMS Questionnaire (NMSQ) score was 7.57. A majority (72.2%) had a score >5, indicating a high NMS burden. The most common NMS noted were nocturia (79%), pain (77.4%), anxiety (57.4%), insomnia (56.5%), depression (42.6%), and apathy (36.5%). The prevalence of various NMS in the study population has been mentioned in Figure 1.

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Figure 1: Prevalence of non-motor symptoms in PD. PD: Parkinson’s disease, RLS: Restless leg syndrome, REMBD: Rapid eye movement behavioral disorder.

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NMSQ positively correlated with age (r = 0.246; p = 0.008), H&Y stage (r = 0.348; p <0.001), and disease duration (r = 0.177; p = 0.05).

Pain prevalence and severity (KPPS)

85.2% of the study population complained of at least one modality of pain. Mean KPPS total score was 30.84.

The assessment using the KPPS revealed varying intensities across its domains. The highest mean scores were recorded in the Radicular (8.00) and Musculocutaneous (7.07) domains. These were followed by moderate scores in Fluctuation-related (4.87), Discoloration (4.19), and Chronic pain (3.22). The lowest impacts were observed in the Nocturnal (2.35) and Orofacial (1.11) categories.

Pain severity distribution is as follows: Mild (0–17): 33%, Moderate (17–68): 57.4%, Severe (>68): 9.6%. The most prevalent form of pain was radicular pain (66.1%), followed closely by musculoskeletal (62.5%) and burning pain in the limbs (31.3%), respectively. Radicular pain also showed the highest maximum severity (51.3%), followed by musculoskeletal pain (40.8%).OFF period dystonic pain was seen in 22.6% and, generalised off period pain in 17.4%, restless legs in 14.8%, and pain associated with dyskinesia in 5.8%.Deep pain or central pain was seen in 17.8%. Bruxism, chewing pain, and burning mouth appear to be less prevalent and have lower severity scores. Figure 2 describes the prevalence and severity scores of different modalities of pain described under KPPS. The prevalence of various domains of KPPS has been described in Figure 3.

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Figure 2: The prevalence and severity scores of different modalities of pain described under KPPS. KPPS: King’s Parkinson’s disease pain scale, RLS: Restless leg syndrome.

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Figure 3: The prevalence of various domains of KPPS. KPPS: King’s Parkinson’s disease pain scale.

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Treatment and pain

Less than half (44, 38%) of the study population were treatment-naive at the time of presentation. Though the prevalence and severity of pain were higher in the treatment-naive group in most domains, no statistically significant difference was noted. Only nocturnal pain showed a statistically significant difference between treated vs untreated groups (p = 0.049), suggesting possible treatment benefit in this group. Table 3 describes the correlation between treatment and KPPS domains. Figure 4 describes the class of antiparkinsonian medications patients were on.

Table 3: Comparison of Hoehn & Yahr severity with the severity of KPPS domains.

H&Y severity staging	KPPS domains	No pain (0)	Mild/moderate pain (<12)	Severe pain (12)	p value
H&Y ≤3	Musculoskeletal pain	36(35.29)	26(25.49)	40 (39.21)	0.341
	Chronic pain	78(76.47)	9(8.82)	15(14.70)	0.649
	Fluctuation-related pain	74(72.54)	9(8.82)	19(18.62)	0.508
	Nocturnal pain	85(83.33)	5(4.90)	12(11.76)	0.101
	Oro-fascial pain	91(89.21)	5(4.90)	6(5.88)	0.122
	Discoloration; Oedema/swelling	67(65.68)	9(8.82)	26(25.49)	0.999
	Radicular pain	35(34.31)	15(14.7)	52(50.98)	0.999
H&Y >3	Musculoskeletal pain	5(38.46)	1(7.69)	7(53.84)	0.341
	Chronic pain	12(92.30)	0	1(7.69)	0.649
	Fluctuation-related pain	8(61.53)	2(15.38)	3(23.07)	0.508
	Nocturnal pain	8(61.53)	1(7.69)	4(30.76)	0.101
	Oro-fascial pain	10(76.92)	0	3(23.07)	0.122
	Discoloration; Oedema/swelling	9(69.23)	1(7.69)	3(23.07)	0.999
	Radicular pain	4(30.76))	2(15.38)	7(53.84)	0.999

p <0.05 is statistically significant. KPPS: King’s Parkinson’s disease pain scale, H&Y: Hoehn and Yahr.

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Figure 4: Antiparkinsonian medications in patients with PD. PD: Parkinson’s disease, COMT: Catechol-O-methyltransferase, MAOB: Monoamine oxidase B.

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Correlates of pain

Significant correlations were noted between KPPS and UPDRS part3: r = 0.218, p = 0.019, KPPS vs. HAM-A (anxiety): r = 0.456, p = 0.041, KPPS vs. HDRS (depression): r = 0.317, p = 0.001. Musculoskeletal pain had a weak negative correlation with disease duration (r = -0.180, p = 0.05), suggesting early onset. Musculoskeletal pain also negatively correlated with LEDD (r = -0.183; p = 0.05), possibly reflecting response to dopaminergic therapy as shown in Table 4. No significant correlations were observed between age, age of onset, or LEDD and most individual KPPS domains. A nonparametric coefficient was used to establish a statistically significant correlation between the various scores. Figure 5 shows the various correlates of pain. When individual domains are compared, no statistically significant correlation was noted with age, duration of PD, age of onset, H&Y staging, and Levodopa dosing. There is a weak positive statistically significant correlation between Hoehn and Yahr (H&Y) staging and nocturnal pain (r = 0.234, p = 0.012). This suggests that as the H&Y stage increases, there tends to be a slight increase in nocturnal pain. Supplementary Table S1 shows the correlation between various patient characteristics and KPPS domains.

Supplementary Table 1

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Table 4: Comparison of treatment with KPPS domains.

Treatment status	Domain	No pain (0) no (%)	Mild/moderate pain (<12)	Severe (>12)	p value
Treatment naive	Musculoskeletal pain	12 (27.27)	11 (25)	21 (47.72)	0.318
	Chronic pain	32 (72.72)	3 (6.81)	9 (20.45)	0.323
	Fluctuation-related pain	31 (70.45)	4 (9)	9 (20.45)	0.952
	Nocturnal pain	32 (72.72)	5 (11.36)	7 (15.9)	0.049
	Oro-fascial pain	39 (88.63)	3 (6.81)	2 (4.54)	0.352
	Discoloration; Oedema/swelling	26 (59.09)	4 (9)	14 (31.81)	0.408
	Radicular pain	12 (27.27)	9 (20.45)	23 (52.27)	0.304
On treatment	Musculoskeletal pain	29 (40.84)	16 (22.53)	26 (39.61)	0.318
	Chronic pain	58 (81.69)	6 (8.45)	7 (9.85)	0.323
	Fluctuation-related pain	51 (71.83)	7 (9.85)	13 (18.3)	0.952
	Nocturnal pain	61 (85.91)	1 (1.4)	9 (12.67)	0.049
	Oro-fascial pain	32 (45.07)	2 (2.81)	7 (9.85)	0.352
	Discoloration; Oedema/swelling	50 (70.42)	6 (8.45)	15 (21.12)	0.408
	Radicular pain	27 (38.02)	8 (11.26)	36 (50.70)	0.304

p <0.05 is statistically significant. KPPS: King’s Parkinson’s disease pain scale

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Figure 5: Various correlates of pain in PD. PD: Parkinson’s disease, HDRS: Hamilton depression rating scale, KPPS: King’s Parkinson’s disease pain scale, HAM-A: Hamilton anxiety rating scale, UPDRS: Unified Parkinson’s disease rating scale.

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DISCUSSION

The prevalence of pain in PD is high, with pain often starting in the body areas experiencing motor symptoms,^[22] however it can also manifest in other areas unaffected by PD and sometimes can manifest years before the diagnosis of PD.^[23,24] Research shows a link between PD and pathophysiological mechanisms of pain. The basal ganglia are involved not only in motor functions but also in the processing of nociceptive and non-nociceptive inputs. It is conceivable that nigrostriatal damage leading to dysfunction of control exerted by the basal ganglia on cerebral areas devoted to processing nociceptive inputs might at least partly account for increased risk of pain in PD.^[25] Hence, PD patients may be predisposed to developing pain.

The prevalence of pain in PD across various studies varies from 24-85%. A striking finding was the high prevalence of pain in our study (85%), highlighting pain as a major NMS in our study population. The varying prevalence of pain in PD in different studies could be explained by the different tools used for pain assessment and the socio-cultural demographics of the different populations being assessed. In our study, the mean KPPS total score was 30.84, with 57.4% experiencing moderate and 9.6% severe pain, highlighting the significant burden of pain in our study population. This is higher than the scores reported in other studies, with the exception of a study by Gao et al., which found a higher score of 41.2 ± 26.8.^[12] The prevalence of musculoskeletal pain in PD patients is significantly higher than in age-matched controls, with studies reporting rates as high as 74%.^[26] Musculoskeletal pain is the most common type of pain in patients with PD arising from muscular, joint, and postural aetiologies.^[9,16,27] However, the most prevalent subtype of pain in our study was radicular pain, which was followed closely by musculoskeletal pain. Radicular pain also showed the highest severity scores, adding significantly to the overall pain burden in PD. Radicular pain, often linked to postural abnormalities and increased muscle tone, affects a notable percentage of PD patients, with studies showing up to 39% having radiculopathy.^[28]

Approximately 40% of PD patients also experience dystonic pain, which can manifest as painful muscle contractions, particularly in the lower limbs.^[14,29] Our study found that 22.6% of patients had dystonic pain during “off” periods, with another 17.4% experiencing generalised “off” period pain. This finding aligns with a Chinese study that reported the prevalence of dystonia-related pain as 27%.^[12] The presence of central pain in 17.8% of our patients highlights the neuropathic dimension of pain in PD.

Studies show that although PD is more common in men, women with PD report experiencing significantly more pain.^[9,10,15] Our research confirms these findings. To note, 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.^[30] This hormonal modulation may explain why pain is a more prominent symptom for women in general, suggesting that gender specific considerations may be warranted in pain management in PD. Both tremor-predominant and akinetic-rigid variants of PD reported a high prevalence of pain in our cohort. Radicular pain and musculoskeletal pain were most common across both groups. Furthermore, studies have shown that individuals with the postural instability and gait difficulty (PIGD) variant report even higher pain scores, highlighting the complexity of pain in PD.^[9,15] A weak positive correlation was noted between UPDRS and KPPS in our study, implying that higher motor scores were associated with more severity and the duration of pain. Similar findings were observed in other studies.^{[10,11,14,15,31]}

Pain is closely related to other NMS, including depression, anxiety, fatigue, and sleep disorders. A moderately positive correlation (r = 0.456) was noted between KPPS and HAM-A, thus establishing that higher severity of pain was associated with higher anxiety. This suggests that as pain severity increases, anxiety symptoms also tend to increase. This establishes the bidirectional relationship between pain and emotional distress, suggesting that treating anxiety may also help manage pain in PD and vice versa. A weak positive correlation (r = 0.317) was noted between KPPS and HDRS, thus establishing that higher severity of pain was associated with higher depressive symptoms. PD patients with pain exhibit higher depression scores and are more likely to have major depression.^[32] When individual domains of KPPS were compared with various demographic and clinical parameters like age, duration of PD, age of onset, and Levodopa dosing, no significant correlation was observed, suggesting that these variables did not directly influence pain in our population. An important observation in this study was that the majority of the study population presented within 2 years of the onset of PD, with 50% being treatment-naive and 88.7% in early disease stages (H&Y ≤3). Similar findings were observed in other studies.^[8] This firmly establishes pain as an early NMS and significantly disabling even in the early course of PD and before the initiation of dopaminergic therapy. A weak negative correlation was observed between musculoskeletal pain and duration of disease, suggesting that musculoskeletal pain may precede or coincide with the motor manifestations of PD. A negative correlation was also observed between musculoskeletal pain and LEDD, possibly suggesting that dopaminergic therapy may also exert a beneficial response to pain. Nocturnal pain showed a statistically significant difference between treated vs untreated groups (p = 0.049), suggesting a possible benefit of antiparkinsonian medications, particularly for nocturnal pain. Dopamine plays a crucial role in modulating pain through both cortical and spinal mechanisms, suggesting that dopaminergic therapy can enhance pain inhibition in PD patients^[33] or have an indirect effect stemming from improved motor function and reduced pain-inducing rigidity or dystonia.

This study utilised the KPPS for a comprehensive assessment of pain in PD patients in a south Indian population. The substantial proportion of treatment-naive patients offers insights into the pain characteristics of PD, minimising the confounding effects of medication. Also, the presence of the majority of patients in the early stages of PD highlights pain as an early NMS, requiring early identification and treatment for better and improved quality of life.

This study is a cross-sectional study; longitudinal studies are needed to understand the progression of pain in patients with PD. The absence of a control group makes it difficult to attribute all the observed characteristics of pain solely to PD. KPPS is a self-reported scale where patients could be subjected to recall bias. Objective pain scales could contribute better to these findings. The absence of data regarding medications used for pain could also be a limitation of the study. Also, the lack of data on co-existent confounding conditions like diabetic neuropathy, osteoarthritis, and spondyloarthropathies may influence the clinical pain profile. Future prospective studies should incorporate comprehensive musculoskeletal and neurological screenings to better isolate these variables. We acknowledge that the use of an English-language questionnaire in a South Indian population presents a potential linguistic barrier. We recognise that the informal translation process, while necessary for data collection in our clinical setting, is a limitation as it was not subjected to a formal cross-cultural validation process.

Routine screening for pain, comprehensive pain assessment, and integrated multidisciplinary management strategies should be initiated at the earliest diagnosis of PD to mitigate its debilitating effects and improve the overall well-being of patients. Future research should focus on elucidating the precise mechanisms of early pain in PD and developing targeted, effective interventions.

CONCLUSION

NMS, particularly pain, is an early manifestation of PD and can be significantly disabling even in the early stages. Pain is significantly associated with female sex, severity of motor symptoms, anxiety, and depression.