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Introduction
Parkinson's disease (PD) presents as a chronic, long-lasting, irreversible condition with symptoms that worsen over time1. PD is usually considered a motor disease; less known and explored are the non-motor symptoms (NMS). These are various and arise in part due to the accumulation of Lewy bodies in regions of the nervous system distinct from the substantia nigra, which can occur even before their detection in the substantia nigra. This explains the occurrence of some non-motor manifestations before the onset of cardinal disease symptoms2. In this context, pain is considered a non-motor symptom.
Many PD patients experience pain at some point during their illness. This complaint is often overlooked because PD is primarily considered a motor disorder. However, for a minority of patients, pain and discomfort can be so debilitating that they dominate the clinical picture1. It is estimated that approximately 10% of individuals have pain as an initial symptom preceding any movement disorder. Furthermore, recently published data suggest that up to 50% of patients experience painful sensations during the course of the disease3.
Pain in PD is often a result of inadequate dopaminergic therapy. Individuals with PD in the "on" state, when the medication is at its maximum effectiveness, report less pain than those in the "off" state1. Individuals with pain and PD exhibit higher scores on depression assessment scales. Therefore, it is important that any assessment of pain in an individual with PD takes into account the possibility of depression contributing to the experience. Another factor to consider is cognitive disorders, which can influence the patient's perception of pain3.
The objective of this study is to determine the prevalence and the most frequent type of pain, as well as its relation to different motor and neuropsychiatric symptoms.
Materials and methods
A cross-sectional study was conducted involving 196 patients diagnosed with PD according to the MDS criteria4 seen at the Movement Disorders Clinic of the National Institute of Neurology and Neurosurgery. A structured questionnaire was administered to all participants after giving informed consent. Data collection spanned from 2021 to 2023, involving expert-led directed interviews during outpatient visits. The variables collected included age, gender, smoking habits, alcohol consumption, anxiety, depression, antiparkinsonian treatment (levodopa, dopaminergic agonists, monoamine oxidase [MAO] inhibitors, and amantadine), intake of antidepressants or antipsychotics, age at symptom onset, age at diagnosis, disease duration, MDS-Unified PD Rating Scale (MDS-UPDRS) item 3.3 score (rigidity item)5, and total MDS-UPDRS score6, where scores were assigned as follows: 0: Never, 1: Rarely (≤ 10% of the time), 2: Sometimes (11–25% of the time), 3: Frequently (26–50% of the time), and 4: Most of the time (≥ 51% of the time).
The MDS-UPDRS consists of four parts, namely I: Non-motor experiences of daily living; II: Motor experiences of daily living; III: Motor examination; IV. Each question is based on five responses that are linked to commonly accepted clinical terms: 0 = normal, 1 = mild, 2 = mild, 3 = moderate, and 4 = severe. The full MDS-UPDRS contains questions/assessments, divided into Part I (13), Part II (13), Part III (33 scores based on 18 items, several with right, left, or other body distribution scores), and Part IV (6). The MDS-UPDRS scores 65 items compared to 55 in the original UPDRS, 48 that had 0-4 options and 7 with yes/no responses.
The MDS Non-Motor Rating Scale (MDS-NMS) L1, 2, 3, and 4 scores (pain-related items)7 were also applied; scores were assigned as follows: L1: muscular, joint, or back pain; L2: deep or dull pain; L3: pain due to abnormal twisting movements of arms, legs, or body; L4: other types of pain (e.g., nocturnal pain and orofacial pain).
The MDS-NMS instrument consists of 30 questions with dichotomous responses, items are grouped into nine domains: Gastrointestinal, urinary tract, sexual function, cardiovascular, apathy/attention/memory, hallucinations/delusions, depression/anxiety/anhedonia, sleep/fatigue, pain, and miscellaneous7.
In addition, the following assessments were performed: QUICK questionnaire 188 for pain presence or improvement after medication dose, Montreal Cognitive Assessment (MOCA)9, Hamilton Depression Scale, Hamilton Anxiety Scale (HAS), King's Parkinson's Disease Pain Scale (KPPS), MDS-UPDRS 4.3 (time in off, and MDS-UPDRS 4.6 (on-dystonia).
Regarding the HAD scale10, scores were assigned as follows: 0-7 points: Normal, 8-13 points: Mild depression, 14-18 points: Moderate depression, 19-22 points: Severe depression, ≥ 23 points: Very severe depression.
For the HAS11, the scores were as follows – 0-17 points: Mild anxiety, 18-24 points: Mild-to-moderate anxiety, 25-30 points: Moderate-to-severe anxiety, and 31-56 points: Very severe anxiety. For the Hamilton Depression and Anxiety scales, obtained scores were classified as follows: Scores < 8 as normal, scores < 14 as mild depression, scores < 19 as moderate depression, scores < 23 as severe depression, and scores > 23 as very severe depression. Similarly, for the anxiety scale, scores < 18 were categorized as mild anxiety, scores < 25 as mild-moderate anxiety, scores < 31 as moderate-severe anxiety, and scores < 57 as very severe anxiety. MOCA questionnaire scores were divided into < 26 for probable mild cognitive impairment and < 16 for probable severe impairment.
The Levodopa Equivalent Dose (LED) was calculated using the formula: (dose in mg of L-dopa × 1) (dose in mg of L-dopa × 0.33 (entacapone) or 0.5 (tolcapone or opicapone) to obtain the COMT inhibitor LED)) + (dose in mg of controlled-release L-dopa × 0.75) + (dose in mg of e×tended-release L-dopa × 0.5) + (dose in mg of pergolide × 100) + (dose in mg of cabergoline × 66) + (dose in mg of cabergoline × 66) + (dose in mg of cabergoline × 66) + (dose in mg of cabergoline × 66) + (dose in mg of cabergoline × 66. mg of cabergoline × 66. 77) + (dose in mg of bromocriptine × 10) + (dose in mg of pramipe×ole × 100) + (dose in mg of ropinirole × 20) + (dose in mg of lisuride × 100) + (dose in mg of dihydroergocryptine × 5) + (dose in mg of lisuride × 100) + (dose in mg of dihydroergocryptine × 5) + (dose in mg of bromocriptine × 5) × 5) + (mg dose of oral selegiline × 10 or sublingual × 80) + (mg dose of rasagiline × 100) +(mg dose of subcutaneous apomorphine × 10 or sublingual apomorphine × 1. 5) + (dose in mg rotigotine × 30) + (dose in mg rotigotine × 30)(dose in mg of piribedil × 1) + (dose in mg of amantadine immediate release × 1 or prolonged release × 1.25) = L-dopa daily dose equivalents12.
The KPPS13 is an evaluator-based scale that assesses pain in PD patients through an interview. It consists of 14 items divided into seven separate domains. Each item is scored for severity (from 0 [no pain] to 3 [very intense pain]) multiplied by frequency (from 0 [never] to 4 [all the time]), resulting in sub-scores ranging from 0 to 12. The sum of these sub-scores gives the total score with a theoretical range of 0-168. The domains and score ranges are as follows: (1) Musculoskeletal pain (range, 0-12); (2) chronic pain (range, 0-24); (3) fluctuation-related pain (range, 0-36); (4) nocturnal pain (range, 0-24); (5) orofacial pain (range, 0–36); (6) discoloration, edema/swelling (range, 0-24); and (7) radicular pain (range, 0-12)14.
Statistical analysis
Patients were categorized according to the MDS-UPDRS item 1.9 (pain)6, patients with pain (Group 1) and non-pain (Group 2). Normality testing was conducted using the Shapiro–Wilk test, resulting in a non-normal distribution. The categorical variables included smoking, alcohol consumption, current treatment, intake of antipsychotics or antidepressants, and self-perceived anxiety or depression, categorized with values of 0 (absence) or 1 (presence). The continuous variables encompass age of onset, age of diagnosis, years of progression, equivalent dose per medication group, equivalent dose of medications per day, NMS-UPDRS total, and NMS-UPDRS 3.3 total.
For the nominal variables, the Chi-squared test was used, and for continuous variables, the T-test or Mann–Whitney U test was used as needed. The statistical analyses were conducted using SPSS software. Statistical significance was set at p < 0.05.
Results
The final sample consisted of 115 males (58.7%) and 81 females (41.3%), with a mean age of 63.56 ± 11.88. The mean disease duration was 7.18 ± 4.9 years. All patients were receiving antiparkinsonian treatment, with 184 on levodopa, 27 on MAO inhibitors, 91 on dopaminergic agonists, and 26 on amantadine (Table 1). Regarding the intake of antidepressants or anxiolytics, 13 were taking anxiolytics and 56 were taking antidepressants.
Table 1 Description of the type of drug in the sample
| Medication type | G1 (n = 139) | G2 (n = 57) | p-value | |
|---|---|---|---|---|
| Levodopa | Levodopa/Carbidopa | 124 | 48 | 0.565 |
| Levodopa/benserazida | 7 | 5 | ||
| MAOI | Rasagiline | 20 | 7 | 0.697 |
| Dopaminergic agonist | Bromocriptine | 3 | 2 | 0.805 |
| Pramipexole | 45 | 14 | ||
| Rotigotine | 19 | 8 | ||
| Amantadine | Amantadine | 21 | 5 | 0.235 |
G1: Parkinson's disease and pain; G2: Parkinson's disease with no pain; MAOI: Monoamine oxidase inhibitor.
Upon conducting the analysis, the following observations were made: Regarding the group of 139 patients with pain, 83 were male and 56 were female (p = 0.645). Group G1 had 92 patients with negative smoking status and 47 with positive smoking status, whereas G2 had 47 with negative smoking status and 10 with positive smoking status (p = 0.23). Positive alcohol consumption was observed in 13 patients and negative in 44 for G2 and 90 were negative with 49 positive for G1 (p = 0.89).
For the self-perceived anxiety variable, we found that in G1, 78 did not have anxiety and 61 did (p = 0.364). On the anxiety scale, for G1, 125 had mild anxiety, 10 had mild-moderate anxiety, and four had moderate-severe anxiety. For G2, 55 had mild anxiety, two had mild-moderate anxiety, and none had moderate-severe anxiety (p = 0.25).
In the self-perceived depression variable, we noted that 79 patients in G1 did not present anxiety and 60 did, whereas in G2, there were 20 patients with anxiety and 37 without it (p = 0.296). In the analysis of the depression scale, for G1, 59 had no depression, 61 had mild depression, 10 had moderate, five had severe, and four had very severe. In G2, 38 had no depression, 15 had mild, four had moderate, and no patient had severe or very severe depression (p = 0.20).
Regarding the analysis of the MOCA questionnaire score, for G1, 29 patients had no impairment, 90 had a mild impairment, and 20 had severe impairment. In G2, 15 had no impairment, 37 had mild impairment, and 5 had severe impairment (p = 0.464).
When performing the analysis of the MDS-UPDRS variable on dystonia and time off, no association was found between groups, detailed information is shown in Table 2. Out of the 139 patients who reported self-perceived pain at the time of the QUICK 18 questionnaire, 83 confirmed again that they were experiencing fluctuating pain. Regarding the improvement in pain with doses of medication, it was found that 55 patients mentioned improvement.
Table 2 Comparison between groups about dystonia and time off
| Variable | G1 (n = 139) | G2 (n = 57) | p-value |
|---|---|---|---|
| Dystonia | |||
| No dystonia | 126 | 52 | 0.316 |
| Minimum | 3 | 4 | |
| Mild | 5 | 2 | |
| Moderate | 4 | 0 | |
| Serious | 1 | 0 | |
| Off time | |||
| No periods | 99 | 39 | 0.843 |
| < 25% | 22 | 10 | |
| 26-50% | 12 | 4 | |
| 51-75% | 6 | 4 |
G1: Parkinson's disease and pain; G2: Parkinson's disease with no pain.
In the MDS-NMS variable L, the most frequently self-perceived types of pain reported by the patients were muscular/joint pain (p < 0.001) and deep/dull pain in the body (p < 0.001).
To compare the total score of the different scales between the groups, we used the Student's t-test where we obtained a significant relationship between depression, anxiety, and the presence of pain. More information is shown in Table 3.
Table 3 Comparison of scales applied between groups
| Variable | GROUP 1 (n = 139) | GROUP 2 (n = 57) | p-value | ||
|---|---|---|---|---|---|
| Mean | SD | Mean | SD | ||
| MDS-UPDRS 3.3 | 34.17 | 14.67 | 32.40 | 15.51 | 0.452 |
| MDS-UPDRS TOTAL | 61.08 | 25.69 | 57.82 | 28.41 | 0.436 |
| MOCA | 20.88 | 5.72 | 21.77 | 4.66 | 0.297 |
| HAD | 9.37 | 5.69 | 5.77 | 4.75 | 0.000 |
| HAS | 9.36 | 6.04 | 6.02 | 4.89 | 0.000 |
MDS-UPDRS: MDS-Unified Parkinson's Disease Rating Scale; MOCA: Montreal cognitive assessment; HAD: Hamilton depression scale; HAS: Hamilton anxiety scale; G1: Parkinson's disease and pain; G2: Parkinson's disease with no pain.
The mean KPPS score was 8.62 ± 10.2. The most associated type of pain in our population was musculoskeletal pain, present in 66.7% of the population, followed by radicular pain (24.2%), pain related to fluctuations (22.7%), chronic pain (20.7%), nocturnal pain (17.2%), discoloration, edema, or swollen pain (14.6%), and orofacial pain (5.6%).
The correlation coefficients for KPPS: Bivariate correlation of the total scores of the KPPS scale and anxiety yielded a Pearson correlation coefficient of 0.320, indicating a moderate correlation (p = 0.000). Similarly, when compared to the depression scale, the Pearson correlation coefficient was 0.381, also indicating a moderate correlation (p = 0.000).
Discussion
The mechanisms underlying pain in PD are unclear. Although some studies have reported that PD patients may have a low pain threshold and tolerance and that they tend to decrease as PD progresses, which may predispose to the development of pain, when we performed our analysis, there was no significant difference in the years of evolution15. Pain can occur at any time during the disease and may be present before diagnosis16.
"KPPS" is a questionnaire with 14 questions covering seven domains: (1) Musculoskeletal pain; (2) chronic pain; (3) pain related to fluctuation; (4) nocturnal pain; (5) orofacial pain; (6) discoloration and edema/swelling; and (7) radicular pain. This is a new approach to pain in PD, which will allow for more in-depth testing in clinical trials for treatments for this aspect of PD17.
It has been observed that all motor symptoms fluctuate, presenting more severe symptoms in the "off" state than in the "on" state but at the time of our analysis, no relationship was found because the patients did not spend so much time in off, although they did report that they noticed an improvement in pain with their medication doses according to the analysis carried out18.
According to several studies, as well as in our population, musculoskeletal pain has been reported to be the most prevalent due to in our population was present in 98 patients19,20. All types of pain were more prevalent in patients with PD in advanced stages than in early stages21, Although in our population, pain in early stages was seen more frequently, this may be due to the fact that patients in advanced stages are often difficult to follow-up.
No association between dystonic or non-dystonic pain has been found in other studies, nor was any association found in this one22. The risk factors for pain in PD include early age of onset, comorbid depressive symptoms, and associated diseases23, we did not take into account the associated diseases but we can see that in the age of our population is no association with early age but there is an association with depressive symptoms.
Although most studies report that pain related to PD is significantly more common in women than in men24, some articles state the opposite25, and this was observed in our study since it was more common in men and no association was found.
Pain patients had significantly more severe depressive symptoms than pain-free patients and pain intensity was associated with more severe depression26, in our study also had an association with depression and anxiety. Some studies mention that as pain intensity increases, quality of life decreases significantly in PD patients27.
Diagnosing the cause of pain requires skill and clinical experience. The most important diagnostic tool is the patient's medical history. Perhaps, the most crucial task for individuals with Parkinson's who experience pain is to describe with the utmost precision whether medications induce, exacerbate, or alleviate their pain1.
The limitations of this study were the lack of information on whether the patient was taking any treatment for pain, the sample was not so large, and most of our patients were in the intermediate stages of the disease so we do not know how it presents in advanced stages, the variables of education or socioeconomic level were not included.
Conclusions
In recent years, nonmotor symptoms in PD have received increasing attention from physicians and researchers. Pain is a heterogeneous symptom in PD. Pain is affected by several factors, e.g., age, sex, depression, severity or duration of illness. Of the disease From the conducted study, it can be observed a significant association between depression and anxiety due to the intensity of pain. In our analysis we found musculoskeletal pain to be the most frequent as seen in the literature. Increased awareness of pain symptoms in PD would provide greater understanding. Further research is needed assessing patients in advanced stages of the disease, including socioeconomic status, pain management, to give a specific analysis that will help us in the majority of PD patients.
