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. 2026 Jan 24;41(5):1221–1232. doi: 10.1002/mds.70194

Types of Pain in Multiple System Atrophy

Nicole Campese 1,2, Mubasher A Qamar 3, Maria Alexandra Chiriac 3,4, Georg Göbel 5, Julia Wanschitz 1, Andreas Schlager 6, Bianca Caliò 1, Fabian Leys 1, Pam Bower 7, Laura Zamarian 1, Anette Schrag 8, Roy Freeman 9, Horacio Kaufmann 10, Roberta Granata 1, Stefan Kiechl 1, Werner Poewe 1, Klaus Seppi 1, Gregor Wenning 1,#, K Ray Chaudhuri 11,12, Alessandra Fanciulli 1,✉
PMCID: PMC13206549  PMID: 41578842

Abstract

Background

Pain affects up to 87% of people with multiple system atrophy (MSA), but it remains unclear which types of pain contribute most to the overall burden.

Objective

To estimate the frequency of different types of pain in MSA individuals.

Methods

In 2023, individuals with MSA completed a web‐based survey that included the King's Parkinson's Disease Pain Questionnaire (KPPQ) and additional questions addressing pain related to MSA core features (eg, coat‐hanger pain, pain due to bladder‐issues, cold extremities, bruises, and pressure sores). Respondents were matched by age, gender, and disease duration with historical cohorts of individuals with Parkinson's disease (PD) and healthy controls (n = 96 each) who had previously completed the KPPQ.

Results

One hundred and fifty‐seven MSA individuals with pain completed the survey. The most frequently reported KPPQ types of pain were nocturnal pain (73%), musculoskeletal pain (63%), and fluctuation‐related pain (62%). Common additional pain sources included coat‐hanger pain (59%), cold extremities (48%), and bruises (44%). All KPPQ pain types were significantly more frequent in MSA than in healthy controls, except for musculoskeletal pain (63% vs. 66%, P = 0.722). Compared with PD, MSA individuals reported less musculoskeletal (63% vs. 78%, P = 0.023), but more orofacial pain (32% vs. 12%, P < 0.001) on the KPPQ.

Conclusions

MSA is associated with both non‐specific and disease‐related pain types, which may be neuropathic, nociceptive, nociplastic, or mixed in nature. These findings inform the development of tailored tools for identifying distinct pain sources in MSA, as each may require a specific therapeutic approach, including targeted treatment of motor and non‐motor symptoms. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: multiple system atrophy, non‐motor symptoms, pain, quality of life

Multiple system atrophy (MSA) is a rare neurodegenerative disorder of the adulthood, characterized by motor impairment and autonomic dysfunction. 1 Based on the predominant motor phenotype, MSA is classified into parkinsonian (MSA‐P) and cerebellar (MSA‐C) subtypes. No therapy currently halts the neurodegenerative process, and management remains symptomatic, targeting the most disabling features. 2

Recent studies have shown that many individuals with MSA (72–87%) experience pain, which significantly interferes with the core activities of daily living, such as work, household chores, and hobbies. 3 , 4

Persons with MSA may experience both acute and chronic pain, the latter typically lasting for more than 3 months. 5 , 6 , 7 According to the International Association for the Study of Pain (IASP), chronic pain is classified as nociceptive, if due to tissue damage, neuropathic, if due to a lesion or dysfunction of the nervous system, or nociplastic, when arising from an altered nociception without evident tissue or nervous system damage. 5 , 6 , 7 Mixed types of pain, in which nociceptive, neuropathic, and nociplastic components coexist, are frequently encountered in clinical practice, despite not being explicitly recognized within the IASP classification framework.

This taxonomy is reflected in the most recent pain classification systems for Parkinson's disease (PD), 8 , 9 , 10 , 11 whereby various types of pain contribute to the overall pain burden, and disease‐specific tools, like the King's Parkinson's Disease Pain Questionnaire (KPPQ), support pain assessment and classification. 12 , 13 , 14 While musculoskeletal, dystonic, and radicular pain have been anecdotally described, the real‐world prevalence of different pain types in MSA remains poorly appraised. 4 , 15 , 16 , 17 , 18 , 19 , 20 No MSA‐specific pain assessment tools are available either, and PD‐derived questionnaires may inadequately capture pain mechanisms related to MSA motor and autonomic features, which may require targeted therapeutic strategies. 15

To address these gaps, we investigated the real‐world frequency of different types of pain in MSA using the KPPQ and assessed additional pain sources commonly associated with core MSA features. We then compared these findings with historical cohorts of individuals with PD and healthy controls.

1. Methods

1.1. Study Design

We analyzed data from a 2023 cross‐sectional, community‐based survey on pain in MSA. 4

Details on the survey methodology are provided elsewhere. 4 , 14 Briefly, informed by a systematic literature review 15 and contributions from a panel of movement disorders, autonomic, and pain experts, as well as four MSA patient and caregiver representatives, a questionnaire assessing the presence and characteristics of pain in MSA was developed through iterative discussions during virtual meetings and subsequent offline draft revisions. The questionnaire was available online in the English and German languages between February and May 2023, and individuals with MSA were invited to participate via social media and patients' advocacies. The 20‐min survey could be completed by the persons with MSA or by a proxy based on their responses. Respondents reporting any kind of pain in the 30 days before survey completion were asked additional questions about the pain quality. Lacking an MSA‐specific pain assessment tool, the survey embedded the KPPQ, consisting of 14 items grouped in seven domains: musculoskeletal, chronic, fluctuation‐related, nocturnal, orofacial, pain related to discoloration, edema or swelling, and shooting pain/pins and needles (or radicular pain). 13 , 14 Since no validated German language version of the KPPQ was available by the time of survey development, 21 this was administered in the original English version and in a German translation prepared by a certified bilingual translator and checked for readability by German‐speaking study team members, patients, and caregivers in a pilot phase of the study.

Additional closed questions explored other potential causes of pain related to core MSA clinical features, including coat‐hanger pain (ie, neck and shoulder pain upon standing due to muscular hypoperfusion in people with orthostatic hypotension 22 ), pain associated with bladder issues, cold hands and feet, 23 pressure sores, and injuries or bruises due to falls. The operational definitions for the abovementioned types of pain are provided in Table S1. 4

1.2. Study Population

1.2.1. Persons with MSA

Survey entries from persons with MSA, based on self‐reported diagnosis, were first assessed for completeness and plausibility. 4 Questionnaires were considered incomplete if not entailing a minimal dataset consisting of age, gender, neurological diagnosis, and information on the presence of pain in the preceding 30 days, or implausible if providing information not consistent with a diagnosis of MSA, as per the 2022 International Parkinson Disease and Movement Disorder Society (MDS) diagnostic criteria and natural history studies (ie, disease onset below 30 years of age, absence of both bradykinesia, ataxia, and autonomic features, and disease duration ≥20 years). 4 , 24 , 25 , 26 Individuals with MSA who had answered the KPPQ and additional questions on MSA‐related sources of pain were included in the present study (Fig. 1).

FIG. 1.

FIG. 1

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Patient selection and matching flowchart. Schematic representation of the selection and matching process applied to persons with multiple system atrophy (MSA), who completed the Innsbruck web‐based pain survey, and to persons with Parkinson's disease (PD) and healthy controls (HCs) from the King's Parkinson's Disease Pain Questionnaire (KPPQ) validation study cohort. The percentage of persons with more than 10 years of education was higher in PD and HCs compared with MSA (92% vs. 77%, P = 0.009 and 96% vs. 77%, P = 0.002, respectively). White ethnicity was slightly overrepresented in the MSA compared with the PD group (93% vs. 79%, P = 0.009). [Color figure can be viewed at wileyonlinelibrary.com]

1.2.2. Persons with PD and Healthy Subjects

To compare the frequency of different types of pain across MSA, PD, and healthy subjects, a historical cohort of healthy subjects and persons with PD, who participated in the KPPQ validation study at King's College London (UK) between 2013 and 2017, was used. All persons with PD to whom the KPPQ was administered had also reported pain in the previous 30 days. In an exploratory analysis, we found a broad heterogeneity in terms of age (P = 0.002) across the overall MSA, PD, and healthy cohort. Disease duration also significantly differed between the MSA and PD subgroups (P = 0.024). For this reason, persons with MSA were retrospectively matched 1:1 with PD and healthy subjects of the historical KPPQ validation cohort following the criteria below:

  • Age ± 3 years

  • Same gender

  • For persons with PD, disease duration ±2 years.

The matching was performed with SPSS v.29.0.0 using the automated optimal matching software function and is summarized in Figure 1. Given the retrospective nature of the analysis, no information on the aforementioned additional pain sources was available for the PD and healthy subjects.

1.3. Statistical Analysis

Qualitative variables were tabulated by frequency (percentage), and quantitative variables by median [25th; 75th percentile]. In the case of missing data, the sample size was reported in square brackets. Qualitative variables were analyzed with Pearson's χ 2 or Fisher–Freeman–Halton test (if n < 5), and quantitative variables with Student's t‐test or Mann–Whitney U test dependent on the distribution.

First, we calculated the frequency of each type of pain identified by the KPPD and of potential causes of pain related to core MSA clinical features. A subgroup analysis was performed to compare the prevalence of each type of pain across MSA‐P and MSA‐C.

For each type of pain, clinical and demographic features of persons with MSA with and without the given type of pain were compared in a univariate fashion. Subsequently, multivariable analyses were performed using binary logistic regression models, and model calibration was evaluated with the Hosmer–Lemeshow goodness‐of‐fit test by comparing observed and expected event rates. The following criteria were applied for inclusion in the multivariable models:

  • P ≤ 0.1 on univariate analysis

  • Adequate sample size and homogeneous distribution (i.e., ≥10 participants per subgroup of 2 × 2 contingency tables).

Models were calculated if at least three variables qualified for inclusion.

Lastly, the frequency of each KPPQ type of pain and domain was compared in a univariate fashion across the subgroups of matched persons with MSA, PD, and healthy subjects. Due to the explorative nature of the study, no correction for multiple testing and no statistical imputation for missing values was applied.

SPSS Statistics v.29.0.0 was used for statistical analysis. Two‐tailed P < 0.05 values were considered statistically significant. Graphs were created with GraphPad Prism v10.1.2.

2. Results

2.1. Study Population

Of the 264 individuals with MSA who accessed our 2023 web‐based survey, 190 were retained after data cleaning. 4 Among individuals with MSA reporting pain (n = 166), 157 completed both the KPPQ and the additional questions on putative MSA‐related pain sources and were included in this study. Sixty‐one percent (n = 95) of the persons with MSA were females, their median age was 62 [55; 69] years, 48% (n = 75) were MSA‐C, 38% (n = 59) were MSA‐P, and 14% (n = 23) had an unspecified clinical phenotype. Individuals with MSA‐P did not differ in any clinical‐demographic characteristic (age, gender, disease duration, education, income, and ethnicity) from those with MSA‐C, except for more frequent use of dopaminergic medications (59% vs. 33%, P = 0.003) (Table 1). Most questionnaires (80%, n = 126) were completed by persons with MSA, 8% (n = 13) by proxies, and for 12% (n = 18) completion details were missing. The majority (82%) of participants completed the English version of the questionnaire, with the remainder completing the German version.

TABLE 1.

Comparison of the clinical‐demographic characteristics and pain types between multiple system atrophy parkinsonian (MSA‐P) and cerebellar (MSA‐C) variant individuals.

Parameter MSA‐P (n = 59) MSA‐C (n = 75) P‐value
Clinical demographic features
Age, years (n = 134) 62 [55; 69] 62 [57; 69] 0.533
Disease duration, years (n = 134) 5 [4; 7] 5 [4; 8] 0.564
Female gender (n = 134) 39 (66) 43 (57) 0.301
Lower annual income (n = 118) 36 (75) 52 (74) 0.930
Higher education (n = 133) 52 (90) 58 (77) 0.062
White ethnicity (n = 134) 54 (92) 70 (93) 0.693
Use of dopaminergic medications (n = 134) 35 (59) 25 (33) 0.003*
KPPQ items
KPPQ1 (n = 133) Pain around joints 38 (64) 47 (64) 0.915
KPPQ2 (n = 133) Pain related to internal organs 24 (41) 21 (28) 0.136
KPPQ3 (n = 132) Generalized pain in the stomach area 18 (31) 21 (28) 0.740
KPPQ4 (n = 133) Pain deep within the body 21 (36) 25 (34) 0.827
KPPQ5 (n = 131) Dyskinetic pain 17 (29) 14 (19) 0.175
KPPQ6 (n = 131) Painful cramps in a region during “off” periods 31 (54) 33 (45) 0.266
KPPQ7 (n = 131) Generalized “off” period pain 22 (39) 21 (28) 0.217
KPPQ8 (n = 132) PLM‐ or RLS‐associated pain 26 (44) 30 (41) 0.731
KPPQ9 (n = 133) Pain whilst turning in bed 37 (63) 42 (57) 0.487
KPPQ10 (n = 133) Pain when chewing 12 (20) 6 (8) 0.041*
KPPQ11 (n = 133) Pain due to grinding teeth 6 (10) 12 (16) 0.344
KPPQ12 (n = 134) Burning sensation in the mouth 5 (9) 9 (12) 0.508
KPPQ13 (n = 133) Burning pain in the limbs 20 (34) 17 (23) 0.162
KPPQ14 (n = 130) Shooting pain/pins and needles 23 (40) 32 (44) 0.583
KPPQ total score (n = 134) 5 [3; 7] 4 [2; 7] 0.167
KPPQ domains
Musculoskeletal pain (n = 133) 38 (64) 47 (64) 0.915
Chronic pain (n = 132) 31 (53) 38 (52) 0.956
Fluctuation‐related pain (n = 130) 39 (67) 41 (57) 0.230
Nocturnal pain (n = 134) 42 (71) 52 (69) 0.816
Orofacial pain (n = 132) 17 (29) 23 (31) 0.826
Discoloration, edema/swelling pain (n = 133) 20 (34) 17 (23) 0.162
Shooting pain/pins and needles (n = 130) 23 (40) 32 (44) 0.583
More pain types (n = 134) 51 (86) 60 (80) 0.326
MSA‐related sources of pain
Coat‐hanger pain (n = 133) 39 (66) 39 (53) 0.119
Pain related to bladder issues (n = 133) 20 (34) 29 (40) 0.491
Bladder infections (n = 133) 14 (24) 21 (28) 0.545
Catheterization (n = 133) 3 (5) 4 (5) 1
Bladder spasms (n = 133) 15 (25) 16 (22) 0.606
Painful cold hands and feet (n = 133) 31 (53) 31 (42) 0.221
Pain related to pressure sores (n = 132) 6 (10) 6 (8) 0.657
Painful injuries/bruises due to falls (n = 134) 27 (46) 33 (44) 0.839
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Note: In cases of missing data, the reference sample size for the variable of interest is reported in brackets. Significant P‐values are reported in bold type and marked with an asterisk (*).

Abbreviations: MSA, multiple system atrophy; MSA‐P, multiple system atrophy, parkinsonian variant; MSA‐C, multiple system atrophy, cerebellar variant; KPPQ, King's Parkinson's Disease Pain Questionnaire; PLM, periodic limb movements; RLS, restless legs syndrome.

Controls were selected from a cohort of 177 PD individuals and 411 healthy subjects. The matched cohorts comprised 96 MSA, 96 PD, and 96 healthy subjects (Fig. 1). In each group, 62% of the participants (n = 59) were females, and the median age was 63 [55; 69] years. The median disease duration was 5 [3; 8] and 5 [4; 8] years for individuals with MSA and PD, respectively (P = 0.340).

2.2. Types of Pain in MSA According to the KPPQ and Associated Clinical‐Demographic Features

Persons living with MSA and experiencing pain (n = 157) reported that, across all body regions, pain developed prior to disease onset in 18% of cases, contemporaneously in 17%, and during the disease course in 65%.

On the KPPQ, MSA respondents mostly complained about pain around the joints (KPPQ1, 63%, n = 98/156), pain whilst turning in bed (KPPQ9, 59%, n = 92/156), and painful cramps during “off” periods (KPPQ6, 48%, n = 74/153) (Fig. 2A). Accordingly, the most common pain domains were nocturnal (73%, n = 114/157), followed by musculoskeletal (63%, n = 98/156) and fluctuation‐related pain (62%, n = 94/152) (Fig. 2B).

FIG. 2.

FIG. 2

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Frequency of different types of pain in the multiple system atrophy (MSA) cohort. Frequency of (A) the 14 King's Parkinson's Disease Pain Questionnaire (KPPQ) items, (B) the seven pain domains identified by the KPPQ, and (C) sources of pain associated with core motor and non‐motor features in the whole MSA cohort (n = 157). [Color figure can be viewed at wileyonlinelibrary.com]

No differences were found across individuals with MSA‐P (n = 59) and MSA‐C (n = 75) in the frequency of any type of pain, except for pain when chewing (KPPQ10), which occurred more frequently in MSA‐P compared with MSA‐C (20% vs. 8%, P = 0.041).

2.2.1. Nocturnal Pain

On univariate analysis, nocturnal pain affected more frequently female compared with male individuals (P = 0.010) (Table S2A). Multivariate analysis confirmed this observation (odds ratio [OR]: 2.584, 95% confidence interval [95% CI]: 1.220–5.476], P = 0.013) (Table S2B).

2.2.2. Musculoskeletal Pain

On univariate comparison, musculoskeletal pain was associated with higher education (P < 0.001), the presence of dystonia (P = 0.034), and breathing problems (P = 0.003) (Table S2A). Individuals with musculoskeletal pain were less frequently on dopaminergic medications than were those without musculoskeletal pain (37% vs. 60%, P = 0.004). This association was retained when focusing on the subgroup of MSA‐P individuals only (47% vs. 81%, P = 0.014). On multivariable analysis, higher education and the use of dopaminergic medications remained significantly associated with the presence of musculoskeletal pain (OR: 3.497, 95% CI: 1.331–9.191, P = 0.011 and OR: 0.306, 95% CI: 0.139–0.674, P = 0.003, respectively) (Table S2B).

Regarding comorbidities, musculoskeletal pain was associated on univariate comparison with the presence of musculoskeletal (P < 0.001), cardiovascular, and gastrointestinal (P = 0.033 and P = 0.044, respectively), and other neurological diseases (P = 0.038) (Table S2A). Multivariate analysis, which excluded musculoskeletal comorbidities due to significant skewness towards individuals with musculoskeletal pain, did not confirm latter associations.

2.2.3. Fluctuation‐Related Pain

Participants reporting fluctuation‐related pain had more frequent dystonia (P < 0.001), recurrent falls (P < 0.001), breathing (P = 0.035), and memory problems (P = 0.018) (Table S2A). Multivariable analysis confirmed an association between fluctuation‐related pain, dystonia, and frequent falls (OR: 3.126, 95% CI: 1.499–6.518, P = 0.002 and OR: 2.810, 95% CI: 1.318–5.993, P = 0.007, respectively) (Table S2B).

Regarding comorbidities, a history of cancer, respiratory, musculoskeletal, and other neurological comorbidities (P = 0.030, P = 0.018, P = 0.024, and P < 0.001, respectively) was associated with the presence of fluctuation‐related pain (Table S2B). These associations were not confirmed by multivariable analysis.

2.3. Other MSA‐Related Painful Sensations and Associated Clinical‐Demographic Features

Regarding MSA‐related sources of pain, 59% (n = 91/155) of participants who had suffered any kind of pain in the previous 30 days reported coat‐hanger pain, 48% (n = 75/156) painful cold hands and feet, and 44% (n = 69/156) painful injuries or bruises due to falls (Fig. 2C).

2.3.1. Coat‐Hanger Pain

On univariate analysis, coat‐hanger pain was significantly associated with dystonia (P = 0.009), postural deformities (P = 0.006), orthostatic intolerance (P = 0.041), and digestive (P < 0.001) and swallowing (P = 0.032) problems (Table S3A). On multivariate analysis, it remained associated with dystonia (OR: 2.110, 95% CI: 1.040–4.282, P = 0.039), postural deformities (OR: 2.723, 95% CI: 1.276–5.812, P = 0.010), orthostatic intolerance (OR: 2.217, 95% CI: 1.022–4.808, P = 0.044), and digestive problems (OR: 2.210, 95% CI: 1.088–4.492, P = 0.028, Table S3B).

2.3.2. Pain Related to Cold Hands and Feet

Painful cold hands and feet showed univariate associations with dystonia (P = 0.005), digestive (P = 0.005) and swallowing (P = 0.039) problems, and with a history of cold hands and feet (P < 0.001, Table S3A). On multivariable analysis, an association was retained for dystonia and digestive problems (OR: 2.146, 95% CI: 1.094–4.209, P = 0.026 and OR: 2.175, 95% CI: 1.111–4.256, P = 0.023, respectively) (Table S3B).

As regards comorbidities, we found a univariate association between painful cold hands and feet and history of psychiatric disease (P = 0.016) (Table S3A). No additional variable qualified for inclusion in a multivariable model.

2.3.3. Pain Related to Injuries or Bruises Due to Falls

On univariate comparison, painful injuries or bruises due to falls were associated with a longer disease duration (P = 0.029), dystonia (P = 0.015), recurrent falls (P < 0.001), and memory problems (P = 0.012) (Table S3A). Multivariable analysis confirmed an association between painful injuries and history of dystonia and frequent falls (OR: 2.315, 95% CI: 1.006–5.329, P = 0.048 and OR: 14.556, 95% CI: 6.386–33.179, P < 0.001, respectively) (Table S3B).

Regarding comorbidities, univariate analysis highlighted an association between pain due to injuries or bruises and respiratory, musculoskeletal, and psychiatric comorbidities (P = 0.010, P = 0.033, and P = 0.027, respectively) (Table S3A), which was not confirmed by multivariable analysis.

2.4. Types of Pain across MSA, PD, and Healthy Subjects

In the matched cohorts, all but two types of pain, that is, pain around the joints (KPPQ1) and burning sensation in the mouth (KPPQ12), occurred more frequently in MSA compared with healthy subjects (Fig. 3A). Pain was more frequent across all KPPQ domains in individuals with MSA compared with healthy controls, except for musculoskeletal pain, which occurred at a similar rate in both groups (63% vs. 66%, P = 0.722; Fig. 3B).

FIG. 3.

FIG. 3

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Frequency of different types of pain across multiple system atrophy (MSA), Parkinson's Disease (PD), and healthy controls (HCs). Comparison of the frequency of (A) the King's Parkinson's Disease Pain Questionnaire (KPPQ) items and (B) different pain domains according to the KPPQ, across age‐, gender‐, and disease‐duration matched cohorts of MSA (n = 96), PD (n = 96), and HCs (n = 96). [Color figure can be viewed at wileyonlinelibrary.com]

Compared with PD individuals, pain around the joints (KPPQ1) was less frequent in MSA (78% vs. 63%, P = 0.023), while pain related to internal organs (KPPQ2), grinding teeth (KPPQ11), and burning sensation in the mouth (KPPQ12) were more common in MSA (P = 0.027, P = 0.017, and P = 0.028, respectively; Fig. 3A). Accordingly, the KPPQ‐domain “musculoskeletal pain” was less frequent in MSA compared with PD (63% vs. 78%, P = 0.023), while the KPPQ‐domain “orofacial pain” was more common (32% vs. 12%, P < 0.001; Fig. 3B).

3. Discussion

Previous research reported pain prevalence in MSA to lay between that of progressive supranuclear palsy and PD. 4 , 27 , 28 , 29 Building on preliminary assessments of the body regions most frequently affected by pain and their putative associations with common clinical features, we here conducted a systematic evaluation of different pain types experienced by individuals with MSA and compared their frequencies with matched PD and healthy control cohorts.

We found that individuals with MSA most frequently reported nocturnal pain, at rates similar to those with PD and at a higher rate than healthy controls. This may reflect shared mechanisms with possible therapeutic implications, including nocturnal akinesia, 30 , 31 restless legs syndrome, 32 and disrupted sympathovagal balance during sleep, which may negatively influence pain pathways. 33 , 34

Musculoskeletal pain was common in MSA but occurred at rates similar to healthy controls, likely reflecting aging or age‐related musculoskeletal conditions. 35 Consistent with studies on PD premotor presentations, musculoskeletal pain was more common in PD than MSA. 36 Nonetheless, in MSA, musculoskeletal pain may also be driven by rigidity, dystonia, postural deformities, and dopaminergic denervation, 15 , 37 as suggested by its onset concurrent with or following motor symptoms in our cohort. Musculoskeletal pain was also associated with dystonia and less frequent dopaminergic use, indicating a potential benefit of dopaminergic therapy, particularly in early disease stages. 38

A large proportion (62%) of MSA individuals in our cohort reported fluctuation‐related pain. Although MSA is traditionally characterized by loss of dopaminergic responsiveness, up to 40% of patients may experience transient benefits and motor fluctuations, particularly early in the disease course. 39 , 40 Prior studies linked on–off fluctuations to increased pain in MSA. 20 Dopaminergic treatment may thus both alleviate musculoskeletal pain and precipitate painful on–off fluctuations or L‐dopa–induced dystonia, underscoring the need for case‐by‐case evaluation of its therapeutic benefits and adverse effects. We observed no difference in fluctuation‐related pain between MSA‐P and MSA‐C individuals, though small sample size, overlapping features, and limitations of self‐reported web‐based information on on–off states may have underpowered this comparison. 4

Orofacial pain occurred in one‐third of MSA individuals, far more frequently than in PD and healthy controls. Painful orofacial dystonia (grimaces), a red‐flag for MSA, may explain this observation. 41 In contrast, shooting pain and paresthesia were similarly prevalent in MSA and PD, likely driven by comorbidities such as polyneuropathy due to aging, long‐term dopaminergic therapy, and peripheral α‐synuclein pathology. 42 , 43 , 44

Many individuals with MSA reported types of pain not captured by the KPPQ but linked to core motor and non‐motor MSA features. Most common was coat‐hanger pain, attributed to cervical and paravertebral muscular hypoperfusion due to orthostatic hypotension. 22 , 45 , 46 We found this pain to be associated with orthostatic intolerance, postural deformities, and dystonia, indicating multiple, overlapping pain triggers in this body region, and supporting a multimodal treatment approach addressing both motor and autonomic dysfunction. 22 , 45 , 46 , 47 Painful vasomotor disturbances in the extremities were also frequently reported. 23 , 48 While cold hands and feet are well described in MSA, their association with pain has been underappreciated to date. 23 Similar to coat‐hanger pain, painful extremities were linked to vasomotor disturbances and dystonia, which may contribute to abnormal posturing, hypoperfusion, discoloration, and pain. 49

Fall‐related complications (eg, bruises or injuries, bladder‐related pain, and pressure sores) were also common causes of pain in MSA. While pain medications may provide partial relief, optimizing the management of both motor and autonomic features, including physiotherapy and occupational therapy to reduce falls, bruises, and sores, may more effectively reduce the overall pain burden in MSA. 4 , 15 , 50

4. Strengths of the Study

This is the first systematic assessment of types of pain affecting persons with MSA. Previous studies were anecdotal reports or retrospective, overlooking motor (e.g., falls) and autonomic (e.g., orthostatic hypotension, bladder issues) contributors, which we found to be significantly associated with the overall pain burden in MSA. 16 , 17 , 18 , 20

This is also the first large‐scale, case–control study comparing types of pain across MSA, PD, and healthy subjects. Earlier work was limited by small samples and lacked systematic pain assessment. 16 , 17 By matching our MSA cohort with historical PD and healthy cohorts, 13 , 14 we identified pain types, such as orofacial pain, that are more frequent in MSA and may reflect core clinical or pathophysiological features.

5. Limitations of the Study

All survey data were patient‐reported, including the KPPQ, without in‐person examination. 4 , 14 Accordingly, MSA diagnoses were self‐reported, though plausibility was checked against consensus criteria and natural history data. 4 , 24 , 25 , 26 , 41 The absence of clinical assessment limited our ability to distinguish nociceptive from neuropathic pain and, unlike the physician‐administered King's Parkinson's Disease Scale, the KPPQ did not enable quantification of pain severity. 13 , 14 At the same time, our patient‐centered, community‐based approach prioritized the subjective pain experience of individuals with MSA and helped to highlight unmet needs, representing an innovative research perspective.

For feasibility reasons, no other validated pain questionnaire was included, preventing comparisons across scales, and as in the original validation study, the KPPQ was only administered to MSA individuals acknowledging pain at survey entry, possibly missing cases who might have positively answered more detailed questions. The KPPQ was used as a checklist of common painful experiences in people with parkinsonism, but it has not been validated in MSA, and some respondents (18%) answered a non‐validated German translation prepared for the purposes of the present study. Pain assessment was limited to the 30 days preceding survey completion, a timeframe shorter than the consensus definition of chronic pain (≥3 months), 5 but consistent with the KPPQ framework. 14 While this time anchor limits an accurate distinction between acute and chronic pain, its alignment with the KPPQ assessment window enabled a direct comparison of the prevalence of different pain types across MSA and historical PD, as well as aging control cohorts. 14 In MSA, the distinction between acute and chronic, or rather recurrent, pain may ultimately prove difficult. Falls or urinary tract infections cause recurrent pain episodes, while coat‐hanger pain may peak in warmer seasons and pain due to cold extremities in colder ones. Since both acute and chronic pain impact on quality of life, they require equal vigilance in clinical practice.

Since the survey was designed for tackling MSA‐specific knowledge gaps, no control group was recruited; instead, we retrospectively matched PD and healthy individuals from the KPPQ validation study. 14 Although questionnaire administration differed (online vs. in‐person) and may have introduced sampling bias, the valuable insights gained from the comparative assessment between the MSA and PD cohorts justified the chosen approach.

Finally, exploratory analyses linking pain types to demographic and clinical features should be interpreted with caution, given significant correlations among clinical‐demographic variables.

6. Towards a Structured Pain Assessment in MSA

While diagnostic accuracy is improving and multiple disease‐modifying candidates are under investigation, pain remains an unmet need in MSA care. 2 , 4 Unlike PD, for which several disease‐specific taxonomies exist, 8 , 9 , 10 , 11 , 13 MSA still lacks a dedicated framework, and heterogeneous systems are used in both research and clinical practice. 15

Distinguishing MSA‐related from unrelated pain is more difficult than in PD: the dopaminergic response is often non‐informative or paradoxical, potentially facilitating nociplastic or mixed pain forms, and advanced parkinsonism may itself facilitate the development of musculoskeletal comorbidities.

Similarly, a clear separation between acute and chronic pain is hindered by recurrent pain episodes associated with falls, bladder problems, and seasonal fluctuations in the severity of types of pain like coat‐hanger pain and cold, painful extremities. Based on these observations, in Figure 4 we propose a preliminary working framework for a structured pain assessment in MSA, prioritizing putative neuropathic, nociceptive, nociplastic, or mixed pathophysiological mechanisms over temporal patterns or presumed disease‐relatedness. This model requires further validation in longitudinal studies, but may improve pain recognition and guide a mechanistic pain management in MSA, likely requiring an optimized treatment of core motor and non‐motor features. 4 , 15 , 50 , 51

FIG. 4.

FIG. 4

Open in a new tab

Types of pain in multiple system atrophy (MSA): a working framework towards a mechanistic classification. CNS, central nervous system. [Color figure can be viewed at wileyonlinelibrary.com]

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

N.C.: 1B, 1C, 2A, 2B, 3A.

M.A.Q: 1B, 2C, 3B.

M.A.C.: 1B, 2C, 3B.

G.G.: 1A, 1B, 1C, 2A, 2B, 3B.

J.W.: 1B, 2C, 3B.

A.Schlager: 1B, 2C, 3B.

B.C.: 1C, 2C, 3B.

F.L.: 1C, 2C, 3B.

P.B.: 2C, 3B.

L.Z.: 1B, 2C, 3B.

A.Schrag: 1B, 2C, 3B.

R.F.: 1B, 2C, 3B.

H.K.: 1B, 2C, 3B.

R.G.: 1B, 2C, 3B.

S.K.: 1B, 2C, 3B.

W.P.: 1B, 2C, 3B.

K.S.: 1B, 2C, 3B.

G.W.: 1A, 1B, 2C.

K.R.C.: 1B, 2C, 3B.

A.F.: 1A, 1B, 1C, 2A, 2B, 3A.

Financial Disclosures of All Authors (for the Preceding 12 Months)

N.C.: Reports speaker fees from the International Parkinson Disease and Movement Disorder Society. M.A.Q.: Nothing to disclose. M.A.C.: Received an EAN Clinical Fellowship Grant. G.G.: Nothing to disclose. J.W.: Reports speaker fees and honoraria for advisory boards from Argenx, Sanofi, Alexion, Euroimmun, Takeda, and Cabaletta Bio, outside of the present work. A.Schlager: Nothing to disclose. B.C.: Nothing to disclose. F.L.: Nothing to disclose. P.B.: Nothing to disclose. L.Z.: Reports honoraria from Novartis and a research grant from EVTZ/Austrian Science Fund (FWF): IPN 135‐B, outside of the present work. A.Schrag: Nothing to disclose. R.F.: Nothing to disclose. H.K.: Editor‐in‐Chief of Clinical Autonomic Research, published by Springer‐Nature, and serves as Principal Investigator (PI) of studies sponsored by Biogen MA Inc. (TRACK MSA, S19‐01846) and Vaxxinity Inc. (UB‐312, S22‐01332). He has received consultant fees from Takeda Pharmaceutical Company Ltd, Ono Pharma UK Ltd, Theravance Biopharma US Inc., and Parexel. He receives royalties from Up To Date. He receives research support from National Institutes of Health‐National Institute of Neurological Disorders and Stroke (NIH‐NINDS), Food & Drug Administration, Familial Dysautonomia Foundation, and HSAN IV Foundation. R.G.: Nothing to disclose. S.K.: Supported by the excellence initiative VASCage (Research Centre on Vascular Ageing and Stroke, project number 898252) of the Austrian Research Promotion Agency FFG (COMET program–Competence Centers for Excellent Technologies) funded by the Federal Ministry for Climate Protection, Environment, Energy, Transport, Innovation and Technology; the Federal Ministry for Labour and Economy; and the federal states Tyrol (via Standortagentur), Salzburg, and Vienna (via Vienna Business Agency). W.P.: Nothing to disclose. K.S.: Nothing to disclose. G.W.: Reports consultancy and lecture fees from Inhibicase, Ono, and Theravance and research grants from the FWF‐Austrian Science Fund, US MSA Coalition, Parkinson Fonds Austria, and the Dr Johannes and Hertha Tuba Foundation, outside of the present work. K.R.C.: Nothing to disclose. A.F.: Reports royalties from Springer Verlag, speaker fees and honoraria from AbbVie, Bial, CNSystems, Desitin, Elsevier, Ferrer, Theravance Biopharma, Medtronic, Sanofi, Austrian Autonomic Society, Austrian Neurology Society, International Parkinson Disease and Movement Disorder Society, and research grants from the FWF‐Austrian Science Fund, Medical University of Innsbruck, Mission MSA (formerly The MSA coalition), and the Dr Johannes and Hertha Tuba Foundation, outside of the present work.

Supporting information

Table S1. Definition and classification of different types of pain assessed in the study. KPPQ, King's Parkinson's Disease Pain Questionnaire; MSA, multiple system atrophy; PLM, periodic limb movements; RLS, restless legs syndrome.

MDS-41-1221-s001.docx (159.2KB, docx)

Table S2. (A) Univariate analysis of the clinical‐demographic characteristics and comorbidities associated with nocturnal, musculoskeletal, fluctuation‐related pain in the multiple system atrophy (MSA) cohort. Significant P‐values are indicated in bold type and marked with an asterisk (*). Due to the explorative nature of the study, no correction for multiple comparisons has been applied. MSA, multiple system atrophy; MSA‐C, multiple system atrophy, cerebellar type; MSA‐P, multiple system atrophy, parkinsonian type; MSA‐nos, multiple system atrophy, not otherwise specified. (B) Binary logistic regression analysis of the clinical‐demographic features associated with nocturnal pain in individuals with MSA. Significant P‐values are indicated in bold type. CI, confidence interval; OR, odds ratio.

MDS-41-1221-s003.docx (39.2KB, docx)

Table S3. (A) Univariate analysis of the clinical‐demographic characteristics and comorbidities associated with coat‐hanger pain, cold hands and feet, and pain due to bruises related to falls in the multiple system atrophy (MSA) cohort. Significant P‐values are indicated in bold type and marked with an asterisk (*). Due to the explorative nature of the study, no correction for multiple comparisons has been applied. MSA, multiple system atrophy; MSA‐C, multiple system atrophy, cerebellar type; MSA‐P, multiple system atrophy, parkinsonian type; MSA‐nos, multiple system atrophy, not otherwise specified. (B) Binary logistic regression analysis of the clinical‐demographic features and comorbidities associated with coat‐hanger pain, cold hands and feet, and pain due to bruises related to falls in the MSA cohort. Significant P‐values are indicated in bold type. CI, confidence interval; OR, odds ratio.

MDS-41-1221-s002.docx (32.6KB, docx)

Acknowledgments

We here acknowledge Alexandra Rizos, Pablo Martinez‐Martin, Claudia Trenkwalder, and Cristian Falup‐Pecurariu from the KPPS and KPPQ validation study steering committee, who coordinated the KPPS and KPPQ validation studies. We also express our gratitude to Lalit Kaltenbach for his technical support in the setup and maintenance of the survey on the REDcap platform and to Miss Marta Siha Behrendt, the founder of “Leben mit MSA/Ein Blog”, and Ms. Cathy Chapman, for their contribution and input during the project purposing phase and for their thoughtful feedback on the questionnaire drafts. Open Access funding provided by Medizinische Universitat Innsbruck/KEMÖ.

Funding agencies: Academic study supported by a Mission MSA seed grant (former MSA Coalition). N.C. was supported by the US MSA Coalition and the Dr Johannes and Hertha Tuba Foundation, and B.C. by the Austrian Science Fund (FWF FG 2700). The authors declare no relevant conflicts of interest related to the present work. Full financial disclosures of all authors are provided in the article.

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.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1. Definition and classification of different types of pain assessed in the study. KPPQ, King's Parkinson's Disease Pain Questionnaire; MSA, multiple system atrophy; PLM, periodic limb movements; RLS, restless legs syndrome.

MDS-41-1221-s001.docx (159.2KB, docx)

Table S2. (A) Univariate analysis of the clinical‐demographic characteristics and comorbidities associated with nocturnal, musculoskeletal, fluctuation‐related pain in the multiple system atrophy (MSA) cohort. Significant P‐values are indicated in bold type and marked with an asterisk (*). Due to the explorative nature of the study, no correction for multiple comparisons has been applied. MSA, multiple system atrophy; MSA‐C, multiple system atrophy, cerebellar type; MSA‐P, multiple system atrophy, parkinsonian type; MSA‐nos, multiple system atrophy, not otherwise specified. (B) Binary logistic regression analysis of the clinical‐demographic features associated with nocturnal pain in individuals with MSA. Significant P‐values are indicated in bold type. CI, confidence interval; OR, odds ratio.

MDS-41-1221-s003.docx (39.2KB, docx)

Table S3. (A) Univariate analysis of the clinical‐demographic characteristics and comorbidities associated with coat‐hanger pain, cold hands and feet, and pain due to bruises related to falls in the multiple system atrophy (MSA) cohort. Significant P‐values are indicated in bold type and marked with an asterisk (*). Due to the explorative nature of the study, no correction for multiple comparisons has been applied. MSA, multiple system atrophy; MSA‐C, multiple system atrophy, cerebellar type; MSA‐P, multiple system atrophy, parkinsonian type; MSA‐nos, multiple system atrophy, not otherwise specified. (B) Binary logistic regression analysis of the clinical‐demographic features and comorbidities associated with coat‐hanger pain, cold hands and feet, and pain due to bruises related to falls in the MSA cohort. Significant P‐values are indicated in bold type. CI, confidence interval; OR, odds ratio.

MDS-41-1221-s002.docx (32.6KB, docx)

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.

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