# The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review

M. Huissoud, M. Boussac, K. Joineau, E. Harroch, C. Brefel-Courbon,

Emeline Descamps

► To cite this version:

M. Huissoud, M. Boussac, K. Joineau, E. Harroch, C. Brefel-Courbon, et al.. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue Neurologique, In press, 10.1016/j.neurol.2023.04.010. hal-04256798

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# The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review

M. Huissoud, M. Boussac, K. Joineau, E. Harroch, C. Brefel-Courbon,

Emeline Descamps

► To cite this version:

M. Huissoud, M. Boussac, K. Joineau, E. Harroch, C. Brefel-Courbon, et al.. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue Neurologique, inPress, 10.1016/j.neurol.2023.04.010. hal-04256798

HAL Id: hal-04256798

https://hal.science/hal-04256798v1

Submitted on 24 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
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General review

# The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review

Q1 M. Huissoud<sup>a,1</sup>, M. Boussac<sup>a,1,*</sup>, K. Joineau<sup>a</sup>, E. Harroch<sup>b</sup>, C. Brefel-Courbon<sup>a,b</sup>, E. Descamps<sup>a,c</sup>

INFO ARTICLE

Article history:

Received 3 February 2023

Received in revised form

19 April 2023

Accepted 23 April 2023

Available online xxx

Keywords:

Parkinson's disease

Non-pharmacological interventions

Pain

Exercises

Physical activities

A B S T R A C T

Chronic pain is a non-motor symptom affecting from 60 to 80% of patients with Parkinson's disease (PD). PD patients can suffer from different types of pain, either specific or not specific of the disease, and depending on various pathophysiological mechanisms (nociceptive, nociplastic or neuropathic), which can be present at any stage of the disease. Non-pharmacological interventions (NPIs) are essential to complement routine care interventions in PD pain management. Moreover, in the literature, it has been shown that 42% of PD patients are already using complementary therapies. Hence, our aim was to investigate the effectiveness and safety of NPIs for pain management in PD. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Eighteen published randomized control trials (RCTs) were included between 2004 and 2021 leading to a total of 976 PD patients. From them, we reported fifteen different NPIs classified in seven categories: physical exercises, balneotherapy, manual therapy, acupuncture, botanical preparation, body-psychological practice and multiprotection care. Our results have shown that NPIs for PD pain management had a low-to-moderate level of evidence showing mainly favourable results, even if some NPIs presented inconclusive results. Moreover, our review highlighted the clinical relevance of some specific NPIs in PD pain management: NPIs consisting of active physical activities, opposed to passive activities. The safety of NPIs was also confirmed since only few minor transient adverse events were reported. Nevertheless, even if some interesting results were found, the methodology of future studies needs to be more robust and to include comprehensive descriptions in order to offer reliable and sound recommendations to clinicians.

© 2023 Elsevier Masson SAS. All rights reserved.

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<footnote><sup>a</sup> Toulouse NeurolImaging Center (ToNIC), University of Toulouse, Inserm UMR1214, University Paul-Sabatier (UPS), Toulouse, France</footnote>

<footnote><sup>b</sup> Department of Clinical Pharmacology and Neurosciences, Centre d'Investigation Clinique (CIC1436), NS-Park/FCRIN Network, Toulouse, France</footnote>

<footnote><sup>c</sup> CNRS, Toulouse, France</footnote>

<footnote>* Corresponding author at: Unité ToNIC, UMR 1214 (Inserm), CHU Purpan, Pavillon Baudot, place du Dr-Joseph-Baylac, 31024 Toulouse cedex 3, France.</footnote>

<footnote>E-mail address: mathilde.boussac@inserm.fr (M. Boussac).</footnote>

<footnote n="1">¹ These both authors contributed equally to this paper.
https://doi.org/10.1016/j.neurol.2023.04.010</footnote>

<footnote>0035-3787/© 2023 Elsevier Masson SAS. All rights reserved.</footnote>
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General review

# The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review

Q1 M. Huissoud<sup>a,1</sup>, M. Boussac<sup>a,1,*</sup>, K. Joineau<sup>a</sup>, E. Harroch<sup>b</sup>, C. Brefel-Courbon<sup>a,b</sup>, E. Descamps<sup>a,c</sup>

INFO ARTICLE

Article history:

Received 3 February 2023

Received in revised form

19 April 2023

Accepted 23 April 2023

Available online xxx

Keywords:

Parkinson's disease

Non-pharmacological interventions

Pain

Exercises

Physical activities

A B S T R A C T

Chronic pain is a non-motor symptom affecting from 60 to 80% of patients with Parkinson's disease (PD). PD patients can suffer from different types of pain, either specific or not specific of the disease, and depending on various pathophysiological mechanisms (nociceptive, nociplastic or neuropathic), which can be present at any stage of the disease. Non-pharmacological interventions (NPIs) are essential to complement routine care interventions in PD pain management. Moreover, in the literature, it has been shown that 42% of PD patients are already using complementary therapies. Hence, our aim was to investigate the effectiveness and safety of NPIs for pain management in PD. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Eighteen published randomized control trials (RCTs) were included between 2004 and 2021 leading to a total of 976 PD patients. From them, we reported fifteen different NPIs classified in seven categories: physical exercises, balneotherapy, manual therapy, acupuncture, botanical preparation, body-psychological practice and multiprotection care. Our results have shown that NPIs for PD pain management had a low-to-moderate level of evidence showing mainly favourable results, even if some NPIs presented inconclusive results. Moreover, our review highlighted the clinical relevance of some specific NPIs in PD pain management: NPIs consisting of active physical activities, opposed to passive activities. The safety of NPIs was also confirmed since only few minor transient adverse events were reported. Nevertheless, even if some interesting results were found, the methodology of future studies needs to be more robust and to include comprehensive descriptions in order to offer reliable and sound recommendations to clinicians.

© 2023 Elsevier Masson SAS. All rights reserved.

16

15

<footnote><sup>a</sup> Toulouse NeurolImaging Center (ToNIC), University of Toulouse, Inserm UMR1214, University Paul-Sabatier (UPS), Toulouse, France</footnote>

<footnote><sup>b</sup> Department of Clinical Pharmacology and Neurosciences, Centre d'Investigation Clinique (CIC1436), NS-Park/FCRIN Network, Toulouse, France</footnote>

<footnote><sup>c</sup> CNRS, Toulouse, France</footnote>

<footnote>* Corresponding author at: Unité ToNIC, UMR 1214 (Inserm), CHU Purpan, Pavillon Baudot, place du Dr-Joseph-Baylac, 31024 Toulouse cedex 3, France.</footnote>

<footnote>E-mail address: mathilde.boussac@inserm.fr (M. Boussac).</footnote>

<footnote n="1">¹ These both authors contributed equally to this paper.
https://doi.org/10.1016/j.neurol.2023.04.010</footnote>

<footnote>0035-3787/© 2023 Elsevier Masson SAS. All rights reserved.</footnote>
## 1. Abbreviation

<table><tr><td>BWSTT</td><td>body weight support treadmill training</td></tr><tr><td>EA</td><td>electro-acupuncture</td></tr><tr><td>JLT</td><td>Jiawei Liujunzi Tang</td></tr><tr><td>LSVT</td><td>Lee Silverman voice treatment</td></tr><tr><td>MBI</td><td>mind-based intervention</td></tr><tr><td>MDT</td><td>multidisciplinary team care</td></tr><tr><td>MPQ</td><td>McGill pain questionnaire</td></tr><tr><td>NMSS</td><td>non-motor symptoms scale</td></tr><tr><td>NPI</td><td>non-pharmacological interventions</td></tr><tr><td>NPIS</td><td>Non-Pharmacological Intervention Society</td></tr><tr><td>NRS</td><td>numeric rating scale</td></tr><tr><td>NW</td><td>Nordic walking</td></tr><tr><td>PD</td><td>Parkinson disease</td></tr><tr><td>PDQ-39</td><td>Parkinson disease questionnaire 39 items</td></tr><tr><td>PICO</td><td>population intervention comparison and outcome</td></tr><tr><td>PRISMA</td><td>preferred reporting items for systematic reviews and meta-analyses</td></tr><tr><td>PT</td><td>physiotherapist</td></tr><tr><td>RCT</td><td>randomized controlled trials</td></tr><tr><td>RoB</td><td>risk of bias</td></tr><tr><td>RODI</td><td>revised Oswestry disability index</td></tr><tr><td>RTM</td><td>rest to music</td></tr><tr><td>SEM</td><td>standard error of the mean</td></tr><tr><td>TIDieR</td><td>template for intervention description and replication</td></tr><tr><td>TT</td><td>tactile touch</td></tr><tr><td>TTM</td><td>therapeutic Thai massage</td></tr><tr><td>VAS</td><td>visual analogue scale</td></tr></table>

## 2. Introduction

Q2 Parkinson's disease (PD) is a neurodegenerative disease characterised by degeneration of the nigrostriatal dopaminergic pathway responsible for motor symptoms (akinesia, resting tremor and rigidity) [1], as well as many non-motor symptoms including sensory disorders such as pain [2,3]. Indeed, chronic pain is experienced by 60 to 80% of PD patients [4]. These painful sensations can emerge from various pathophysiological mechanisms (nociceptive, nociplastic and neuropathic pain [5,6]), and can be present at any stage of the disease. Indeed, pain in PD may arise from numerous pathways such as both central and peripheral degeneration [7], as well as specific cortical plasticity and/or connectivity [8] or even anatomical changes in brain structures involved in nociceptive mechanisms [9]. Inherently, chronic pain is a multidimensional perception with a major biopsychosocial impact responsible for a decrease in patients' quality of life, professional activity and social ties [10].

There are different pain subtypes in PD patients and it has been proposed to classify pain in PD into nociceptive, neuropathic and nociplastic pain, either specific or unspecific to PD [5,6]. This classification is of importance since specific types of pain may respond differently to diverse treatments: for example, it is known that musculoskeletal PD pain can be alleviated by lévodopa [11], which is not true for every

PD-related pain. A meta-analysis suggests that the increased prevalence and intensity of clinical pain complaints in PD may be, at least in part, influenced by abnormal nociceptive processing [12]. Functional imaging have shown an hyperactivation of the median pain pathway (affective pathway) in PD patients with chronic central pain compared to PD patients without pain during an acute pain stimulus, suggesting physiological mechanisms proper to PD chronic pain [13]. Several neurotransmitters such as dopamine, norepinephrine, serotonin, and opioids could participate in abnormal pain processing in PD [14].

Currently, the usual dopaminergic treatments to address PD symptoms are not effective enough for pain [15]. In addition, conventional analgesic approaches may not relieve PD pain [16]. For example, oxycodone (a strong-acting opioid analgesic) induced a significant pain reduction in PD patients at 4, 8 and 12 weeks compared to placebo, but this diminution did not reach significance at 16 weeks, while leading to some treatment-related side effects [17]. Hence, long-time effect of analgesic in PD may be insufficient. Hence, pain remains a major issue for the concerned patients [18]. In addition, despite deep brain stimulation of the subthalamic nuclei increasing heat pain threshold in PD patients with pain and therefore decreasing painful sensations [19] and some pharmacological clinical trials demonstrating an effect on pain in PD [20-24], most studies had shown insignificant or insufficient results. Therefore, the management of PD pain remains challenging and non-pharmacological interventions (NPIs) should be considered in the context of evidence-based treatments. Evidence-based NPIs are safe and effective components of holistic pain care, which may also be a strategy to reduce the analgesics consumption [25], especially since NPIs were defined as an essential add-on to routine care interventions in PD pain management [26,27]. Moreover, in the literature, it has been shown that 42% of PD patients were already using complementary therapies [28,29]. As a result, there is growing interest in complementary therapies among medical staff and a need for researchers to provide evidence of efficacy and safety.

Furthermore, NPIs have the ability to induce interdependent benefits: reducing pain, anxiety, depression, nausea, facilitating restful sleep, increasing well-being etc., as seen in fibromyalgia [30], which is a huge advantage compared to most pharmacological treatments. It also appears that, while medication-only treatment strategies may promote passive coping processes, the benefits of NPIs would emerge in part through a process of patient empowerment, active problem solving, realistic goal setting and a functional/rehabilitative perspective [31]. In addition, recent evidence has suggested that targeted NPIs, as well as some other non-motor symptom management options could have a significant beneficial effect on quality of life and should be considered in PD treatments [32].

Despite this growing interest in NPIs, evidence for the effectiveness of these practices in PD pain management is generally limited in randomised controlled trials (RCT) [33]. Implementation of positive trial findings is often slow because clinicians perceive the results as either limited, invalid, or irrelevant to their patients. Another barrier is clinicians' ability to suggest treatment based on the information provided in the

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## 1. Abbreviation

<table><tr><td>BWSTT</td><td>body weight support treadmill training</td></tr><tr><td>EA</td><td>electro-acupuncture</td></tr><tr><td>JLT</td><td>Jiawei Liujunzi Tang</td></tr><tr><td>LSVT</td><td>Lee Silverman voice treatment</td></tr><tr><td>MBI</td><td>mind-based intervention</td></tr><tr><td>MDT</td><td>multidisciplinary team care</td></tr><tr><td>MPQ</td><td>McGill pain questionnaire</td></tr><tr><td>NMSS</td><td>non-motor symptoms scale</td></tr><tr><td>NPI</td><td>non-pharmacological interventions</td></tr><tr><td>NPIS</td><td>Non-Pharmacological Intervention Society</td></tr><tr><td>NRS</td><td>numeric rating scale</td></tr><tr><td>NW</td><td>Nordic walking</td></tr><tr><td>PD</td><td>Parkinson disease</td></tr><tr><td>PDQ-39</td><td>Parkinson disease questionnaire 39 items</td></tr><tr><td>PICO</td><td>population intervention comparison and outcome</td></tr><tr><td>PRISMA</td><td>preferred reporting items for systematic reviews and meta-analyses</td></tr><tr><td>PT</td><td>physiotherapist</td></tr><tr><td>RCT</td><td>randomized controlled trials</td></tr><tr><td>RoB</td><td>risk of bias</td></tr><tr><td>RODI</td><td>revised Oswestry disability index</td></tr><tr><td>RTM</td><td>rest to music</td></tr><tr><td>SEM</td><td>standard error of the mean</td></tr><tr><td>TIDieR</td><td>template for intervention description and replication</td></tr><tr><td>TT</td><td>tactile touch</td></tr><tr><td>TTM</td><td>therapeutic Thai massage</td></tr><tr><td>VAS</td><td>visual analogue scale</td></tr></table>

## 2. Introduction

Q2 Parkinson's disease (PD) is a neurodegenerative disease characterised by degeneration of the nigrostriatal dopaminergic pathway responsible for motor symptoms (akinesia, resting tremor and rigidity) [1], as well as many non-motor symptoms including sensory disorders such as pain [2,3]. Indeed, chronic pain is experienced by 60 to 80% of PD patients [4]. These painful sensations can emerged from various pathophysiological mechanisms (nociceptive, nociplastic and neuropathic pain [5,6]), and can be present at any stage of the disease. Indeed, pain in PD may arise from numerous pathways such as both central and peripheral degeneration [7], as well as specific cortical plasticity and/or connectivity [8] or even anatomical changes in brain structures involved in nociceptive mechanisms [9]. Inherently, chronic pain is a multidimensional perception with a major biopsychosocial impact responsible for a decrease in patients' quality of life, professional activity and social ties [10].

There are different pain subtypes in PD patients and it has been proposed to classify pain in PD into nociceptive, neuropathic and nociplastic pain, either specific or unspecific to PD [5,6]. This classification is of importance since specific types of pain may respond differently to diverse treatments: for example, it is known that musculoskeletal PD pain can be alleviated by lévodopa [11], which is not true for every

PD-related pain. A meta-analysis suggests that the increased prevalence and intensity of clinical pain complaints in PD may be, at least in part, influenced by abnormal nociceptive processing [12]. Functional imaging have shown an hyperactivation of the median pain pathway (affective pathway) in PD patients with chronic central pain compared to PD patients without pain during an acute pain stimulus, suggesting physiological mechanisms proper to PD chronic pain [13]. Several neurotransmitters such as dopamine, norepinephrine, serotonin, and opioids could participate in abnormal pain processing in PD [14].

Currently, the usual dopaminergic treatments to address PD symptoms are not effective enough for pain [15]. In addition, conventional analgesic approaches may not relieve PD pain [16]. For example, oxycodone (a strong-acting opioid analgesic) induced a significant pain reduction in PD patients at 4, 8 and 12 weeks compared to placebo, but this diminution did not reach significance at 16 weeks, while leading to some treatment-related side effects [17]. Hence, long-time effect of analgesic in PD may be insufficient. Hence, pain remains a major issue for the concerned patients [18]. In addition, despite deep brain stimulation of the subthalamic nuclei increasing heat pain threshold in PD patients with pain and therefore decreasing painful sensations [19] and some pharmacological clinical trials demonstrating an effect on pain in PD [20–24], most studies had shown insignificant or insufficient results. Therefore, the management of PD pain remains challenging and non-pharmacological interventions (NPIs) should be considered in the context of evidence-based treatments. Evidence-based NPIs are safe and effective components of holistic pain care, which may also be a strategy to reduce the analgesics consumption [25], especially since NPIs were defined as an essential add-on to routine care interventions in PD pain management [26,27]. Moreover, in the literature, it has been shown that 42% of PD patients were already using complementary therapies [28,29]. As a result, there is growing interest in complementary therapies among medical staff and a need for researchers to provide evidence of efficacy and safety.

Furthermore, NPIs have the ability to induce interdependent benefits: reducing pain, anxiety, depression, nausea, facilitating restful sleep, increasing well-being etc., as seen in fibromyalgia [30], which is a huge advantage compared to most pharmacological treatments. It also appears that, while medication-only treatment strategies may promote passive coping processes, the benefits of NPIs would emerge in part through a process of patient empowerment, active problem solving, realistic goal setting and a functional/rehabilitative perspective [31]. In addition, recent evidence has suggested that targeted NPIs, as well as some other non-motor symptom management options could have a significant beneficial effect on quality of life and should be considered in PD treatments [32].

Despite this growing interest in NPIs, evidence for the effectiveness of these practices in PD pain management is generally limited in randomised controlled trials (RCT) [33]. Implementation of positive trial findings is often slow because clinicians perceive the results as either limited, invalid, or irrelevant to their patients. Another barrier is clinicians' ability to suggest treatment based on the information provided in the

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published reports. Comprehensive descriptions of NPIs that allow their replication, as well as easily available information, would allow greater transferability of published research in clinical practice.

## 2.1. Aim

To investigate effectiveness and safety of NPIs in PD pain management, and to identify criteria for improvement in the scientific literature, using a systematic review.

# 3. Material and methods

## 3.1. Search strategy and information sources

This systematic review was conducted in accordance with the PRISMA statement [34]. First, the literature was screened on NPIs in PD pain to define our search terms. To identify the largest number of potentially eligible studies as possible, we determined the population intervention comparison and outcome (PICO) criteria as search terms, as described in the Cochrane handbook [35] (Table 1). The review was registered on PROSPERO in February 2022 (ID number: 309266).

In order to conduct a systematic review, we submitted our search terms in a broad panel of the database to consider the multimodal aspect of pain (biopsychosocial model). Between December 2021 and March 2022, the following databases were independently searched by two authors (M.H. and M.B.): PubMed, Cochrane, PEDro, Embase, Web of science, American Psychological Association (APA), Cairn, Pascal et Francis, Campbell Collaboration and LiSSa. This search strategy was supplemented by a manual search of reference lists of relevant included articles and reviews. Moreover, since non-invasive neuromodulation strategies are not always referenced as NPIs, we did a supplementary research in PubMed using the following keywords: “pain” and “Parkinson” and “transcranial stimulation”, filtered for “Randomized Controlled Trial” and “Adult: 19+ years”.

## 3.2. Eligibility criteria

Studies were included if they were clinical RCTs, with pain assessment as a primary or secondary outcome, on patients diagnosed with PD, treated with a NPI as defined by the Non-

Pharmacological Intervention Society (NPIS) meaning “non-pharmacological, targeted and non-invasive, evidence-based intervention on a person to prevent, care or cure” [36]. Only studies published in English or French were included. No exclusion criteria were defined based on age or stage of disease but clinical trials with patients undergoing surgical treatment for PD (deep brain stimulation or pallidotomy) were excluded since there are considered as invasive interventions. The search results were then redefined using ‘human studies’ and ‘+18 adults’ boundaries.

The only outcome we studied in this review was pain (chronic or not), thus we selected clinical trials, which assessed pain with measurement tools at any time point of the protocol. Studies using either specific [visual analogue scale (VAS)] or non-specific measurement tools in the assessment of pain [such as the Parkinson disease questionnaire 39 items (PDQ-39)] were included. All studies that mentioned pain without assessing it were excluded.

## 3.3. Study selection process

The steps of the selection process were depicted in the PRISMA diagram (Fig. 1), all steps were independently scrutinized by two authors (M.H. and M.B.). The results with identified search terms were collected from the databases described above, the first selection was made with the title of the articles, excluding articles with non-PD patients, articles about pharmacological or surgical interventions and duplicates, for the main screening as well as the non-invasive neuromodulation supplementary search. Then, the abstracts were screened to exclude those that did not correspond to our eligibility criteria. To ensure that all relevant articles on PD pain management by NPI were identified, the bibliography of each article was also screened for the detection of any supplementary related publications. Then we added the matching ones to our list of selected articles. Finally, we performed a last sorting by reading the whole set of articles to exclude the last doubts about their correspondence to our criteria. All disagreements were resolved by discussion to reach a consensus.

## 3.4. Data extraction

Data extraction was performed by the two authors (M.H., M.B.) who reviewed and selected all identified relevant articles, and is available on an adapted structured template in two tables: (i) author name and year of publication, name of the intervention, planning and description of intervention and control intervention, description of population, duration of the studies (Table 2); (ii) study design (blinded), type of pain assessment, functional state (ON or OFF states), the template for intervention description and replication (TIDieR) list completion, adverse events, and statistical results on pain outcomes (Table 3).

To compare the reproducibility of interventions, the TIDieR quality criterion was chosen [37]. The TIDieR list – as published by the CONSORT group [38] in 2010 – includes questions that focus on the precise and specific description of intervention elements. The list requests multiple information: a brief description of the intervention (No. 1), a theoretical rationale

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<table><caption>Table 1 – PICO Criteria.</caption><thead><tr><td>Criteria</td><td>Search terms</td></tr></thead><tbody><tr><td>Population</td><td>(Parkinson disease[MeSH Terms]) OR (Parkinson's disease[MeSH Terms]) OR (parkinson)</td></tr><tr><td>Intervention</td><td>(acupuncture[MeSH Terms]) OR (physiotherapy) OR (complementary therapy) OR (multidisciplinary care) OR (non-pharmacological) OR (integrative care) OR (exercise) OR (massage) OR (music)</td></tr><tr><td>Comparison</td><td>Clinical trials</td></tr><tr><td>Outcome</td><td>(chronic pain[MeSH Terms]) OR (pain) OR (pain management)</td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023), https://doi.org/10.1016/j.neurol.2023.04.010
published reports. Comprehensive descriptions of NPIs that allow their replication, as well as easily available information, would allow greater transferability of published research in clinical practice.

## 2.1. Aim

To investigate effectiveness and safety of NPIs in PD pain management, and to identify criteria for improvement in the scientific literature, using a systematic review.

# 3. Material and methods

## 3.1. Search strategy and information sources

This systematic review was conducted in accordance with the PRISMA statement [34]. First, the literature was screened on NPIs in PD pain to define our search terms. To identify the largest number of potentially eligible studies as possible, we determined the population intervention comparison and outcome (PICO) criteria as search terms, as described in the Cochrane handbook [35] (Table 1). The review was registered on PROSPERO in February 2022 (ID number: 309266).

In order to conduct a systematic review, we submitted our search terms in a broad panel of the database to consider the multimodal aspect of pain (biopsychosocial model). Between December 2021 and March 2022, the following databases were independently searched by two authors (M.H. and M.B.): PubMed, Cochrane, PEDro, Embase, Web of science, American Psychological Association (APA), Cairn, Pascal et Francis, Campbell Collaboration and LiSSa. This search strategy was supplemented by a manual search of reference lists of relevant included articles and reviews. Moreover, since non-invasive neuromodulation strategies are not always referenced as NPIs, we did a supplementary research in PubMed using the following keywords: “pain” and “Parkinson” and “transcranial stimulation”, filtered for “Randomized Controlled Trial” and “Adult: 19+ years”.

## 3.2. Eligibility criteria

Studies were included if they were clinical RCTs, with pain assessment as a primary or secondary outcome, on patients diagnosed with PD, treated with a NPI as defined by the Non-

Pharmacological Intervention Society (NPIS) meaning “non-pharmacological, targeted and non-invasive, evidence-based intervention on a person to prevent, care or cure” [36]. Only studies published in English or French were included. No exclusion criteria were defined based on age or stage of disease but clinical trials with patients undergoing surgical treatment for PD (deep brain stimulation or pallidotomy) were excluded since there are considered as invasive interventions. The search results were then redefined using ‘human studies’ and ‘+18 adults’ boundaries.

The only outcome we studied in this review was pain (chronic or not), thus we selected clinical trials, which assessed pain with measurement tools at any time point of the protocol. Studies using either specific [visual analogue scale (VAS)] or non-specific measurement tools in the assessment of pain [such as the Parkinson disease questionnaire 39 items (PDQ-39)] were included. All studies that mentioned pain without assessing it were excluded.

## 3.3. Study selection process

The steps of the selection process were depicted in the PRISMA diagram (Fig. 1), all steps were independently scrutinized by two authors (M.H. and M.B.). The results with identified search terms were collected from the databases described above, the first selection was made with the title of the articles, excluding articles with non-PD patients, articles about pharmacological or surgical interventions and duplicates, for the main screening as well as the non-invasive neuromodulation supplementary search. Then, the abstracts were screened to exclude those that did not correspond to our eligibility criteria. To ensure that all relevant articles on PD pain management by NPI were identified, the bibliography of each article was also screened for the detection of any supplementary related publications. Then we added the matching ones to our list of selected articles. Finally, we performed a last sorting by reading the whole set of articles to exclude the last doubts about their correspondence to our criteria. All disagreements were resolved by discussion to reach a consensus.

## 3.4. Data extraction

Data extraction was performed by the two authors (M.H., M.B.) who reviewed and selected all identified relevant articles, and is available on an adapted structured template in two tables: (i) author name and year of publication, name of the intervention, planning and description of intervention and control intervention, description of population, duration of the studies (Table 2); (ii) study design (blinded), type of pain assessment, functional state (ON or OFF states), the template for intervention description and replication (TIDieR) list completion, adverse events, and statistical results on pain outcomes (Table 3).

To compare the reproducibility of interventions, the TIDieR quality criterion was chosen [37]. The TIDieR list – as published by the CONSORT group [38] in 2010 – includes questions that focus on the precise and specific description of intervention elements. The list requests multiple information: a brief description of the intervention (No. 1), a theoretical rationale

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<table><caption>Table 1 – PICO Criteria.</caption><thead><tr><td>Criteria</td><td>Search terms</td></tr></thead><tbody><tr><td>Population</td><td>(Parkinson disease[MeSH Terms]) OR (Parkinson's disease[MeSH Terms]) OR (parkinson)</td></tr><tr><td>Intervention</td><td>(acupuncture[MeSH Terms]) OR (physiotherapy) OR (complementary therapy) OR (multidisciplinary care) OR (non-pharmacological) OR (integrative care) OR (exercise) OR (massage) OR (music)</td></tr><tr><td>Comparison</td><td>Clinical trials</td></tr><tr><td>Outcome</td><td>(chronic pain[MeSH Terms]) OR (pain) OR (pain management)</td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023), https://doi.org/10.1016/j.neurol.2023.04.010
<figure><img src="image_2.png" /></figure>

Fig. 1 – Flowchart of studies selections following PRISMA recommendations. PEDRO: Physiotherapy Evidence Database; APA: American Psychological Association. Some supplementary databases were used (Cochrane, Cairn, Pascal et Francis, Campbell Collaboration and LiSSa) but no titles were identified through their use, so there are not presented in the flowchart.

for the choice of the intervention (No. 2: why?), the equipment (No. 3) and procedure needed (No. 4), the person who provided the intervention (No. 5), the context i.e. whether the interventions are held in a group or individual session (No. 6: how), the place where it is held (No. 7), and finally the scheduling of the sessions (No. 8: when and how many).

Any missing data or unclear information were reported as such in the template.

## 3.5. Data presentation

We represented our results in two tables: Table 2 presents demographic information of the selected articles and the Table 3 displays information related to the NPI and their outcomes on PD pain management. After studies selection, interventions were categorised according to the NPIS classification (available on their website [36] and recently defined in

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<figure><img src="image_2.png" /><figcaption>Fig. 1 – Flowchart of studies selections following PRISMA recommendations. PEDRO: Physiotherapy Evidence Database; APA: American Psychological Association. Some supplementary databases were used (Cochrane, Cairn, Pascal et Francis, Campbell Collaboration and LiSSa) but no titles were identified through their use, so there are not presented in the flowchart.</figcaption></figure>

for the choice of the intervention (No. 2: why?), the equipment (No. 3) and procedure needed (No. 4), the person who provided the intervention (No. 5), the context i.e. whether the interventions are held in a group or individual session (No. 6: how), the place where it is held (No. 7), and finally the scheduling of the sessions (No. 8: when and how many).

Any missing data or unclear information were reported as such in the template.

### 3.5. Data presentation

We represented our results in two tables: Table 2 presents demographic information of the selected articles and the Table 3 displays information related to the NPI and their outcomes on PD pain management. After studies selection, interventions were categorised according to the NPIS classification (available on their website [36] and recently defined in

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<table><caption>Table 2 – Characteristics of studies.</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td rowspan="3">Schaible et al., 2021</td><td rowspan="3">Intervention</td><td>Lee Silverman Voice Treatment (LSVT)-BIG training</td><td rowspan="3">Active</td><td rowspan="3">16 individual sessions of 60 min; 4 times a week for 4 weeks by a LSVT-BIG qualified physiotherapist (PT)</td><td>Standardized multidirectional whole-body movements performed with maximal amplitude of reaching and stepping</td><td>14</td><td>63.3 ± 8.5</td><td>2.0 ± 0.7</td><td>5.4 ± 2.6</td><td>4 (+ follow-up 4)</td></tr><tr><td>Intensive physiotherapy with an individual training plan</td><td>Instructions were to work with at least 60% to 80% of their maximal effort, special focus was made on assessment of individual deficits, gait, falls, freezing of gait and dexterity</td><td>13</td><td>66.2 ± 8.7</td><td>1.7 ± 0.7</td><td>5.3 ± 3.4</td><td></td></tr><tr><td>Comparator (sham)</td><td>Regular physiotherapy</td><td>16 individual sessions of 60 min; 2 times a week for 8 weeks</td><td>12</td><td>65.5 ± 8.2</td><td>2.1 ± 0.4</td><td>5.4 ± 4.2</td><td></td></tr><tr><td rowspan="2">Myers et al., 2020</td><td rowspan="2">Intervention</td><td rowspan="2">Vinyasa Yoga</td><td rowspan="2">Active</td><td rowspan="2">20 to 24 sessions in groups of 7 to 9 participants by two certified Yoga instructors; twice a week</td><td>Introduction with relaxation and guided meditation, gentle spinal movements, standing poses (Warrior I and II, Crescent Lunge, Downward Dog, and Tree), cool down, and rest and relaxation</td><td>13</td><td>70.5 ± 8.7</td><td>2 [2; 3]</td><td>-</td><td>12</td></tr><tr><td>-</td><td>13</td><td>65.0 ± 8.7</td><td>2 [2; 3]</td><td>-</td><td></td></tr><tr><td rowspan="2">Gandolfi et al., 2019</td><td rowspan="2">Comparator (control)</td><td rowspan="2">Usual daily routines</td><td rowspan="2">Trunk-specific rehabilitation</td><td rowspan="2">30 individual sessions of 60 min; 5 days a week for 4 weeks by PT</td><td>(1) Active self-correction exercises with visual feedback (i.e. mirror), with proprioceptive feedback (i.e. EMG feed-back), and without any feedback</td><td>19</td><td>72.4 ± 6.4</td><td>3 [1.5; 3]</td><td>8.01 ± 5.9</td><td>4 (+ follow-up 4)</td></tr><tr><td>(2) Trunk stabilization exercises (3) Functional tasks were used as the element of "distraction" (i.e. dual-task exercises) that engaged the patient's attention and induced them to maintain unconsciousness of the self-correction and trunk stabilization and reduce functional impairment</td><td>18</td><td>70.7 ± 6.6</td><td>2 [1.4; 3]</td><td>6.6 ± 4.3</td><td></td></tr><tr><td rowspan="2">Atan et al., 2019</td><td rowspan="2">Intervention</td><td rowspan="2">Body Weight Support Treadmill Training (BWSTT) with reduction of body weight of 20% 10% BWSTT</td><td rowspan="2">Active</td><td rowspan="2">30 individual sessions of 60 min; 5 days a week by PT</td><td>Joint mobilization, muscle strengthening and stretching, overground gait training and balance exercises</td><td>10</td><td>68.6 ± 8.2</td><td>2.6 ± 0.7</td><td>5.6 ± 5.3</td><td>6</td></tr><tr><td>Half a session for rehabilitation and the other half for BWSTT</td><td>10</td><td>72.2 ± 7.9</td><td>2.8 ± 0.6</td><td>9.8 ± 9.0</td><td></td></tr><tr><td></td><td>Comparator (sham)</td><td>0% BWSTT (patients are on the treadmill)</td><td></td><td></td><td></td><td>10</td><td>69.7 ± 8.0</td><td>2.7 ± 0.7</td><td>7.6 ± 6.4</td><td></td></tr></tbody></table>
<table><caption>Table 2 – Characteristics of studies.</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td rowspan="3">Schaible et al., 2021</td><td rowspan="3">Intervention</td><td>Lee Silverman Voice Treatment (LSVT)-BIG training</td><td rowspan="3">Active</td><td rowspan="3">16 individual sessions of 60 min; 4 times a week for 4 weeks by a LSVT-BIG qualified physiotherapist (PT)</td><td>Standardized multidirectional whole-body movements performed with maximal amplitude of reaching and stepping</td><td>14</td><td>63.3 ± 8.5</td><td>2.0 ± 0.7</td><td>5.4 ± 2.6</td><td rowspan="3">4 (+ follow-up 4)</td></tr><tr><td>Intensive physiotherapy with an individual training plan</td><td>Instructions were to work with at least 60% to 80% of their maximal effort, special focus was made on assessment of individual deficits, gait, falls, freezing of gait and dexterity</td><td>13</td><td>66.2 ± 8.7</td><td>1.7 ± 0.7</td><td>5.3 ± 3.4</td></tr><tr><td>Comparator (sham)</td><td>Regular physiotherapy</td><td>16 individual sessions of 60 min; 2 times a week for 8 weeks</td><td>12</td><td>65.5 ± 8.2</td><td>2.1 ± 0.4</td><td>5.4 ± 4.2</td></tr><tr><td rowspan="2">Myers et al., 2020</td><td rowspan="2">Intervention</td><td rowspan="2">Vinyasa Yoga</td><td rowspan="2">Active</td><td rowspan="2">20 to 24 sessions in groups of 7 to 9 participants by two certified Yoga instructors; twice a week</td><td>Introduction with relaxation and guided meditation, gentle spinal movements, standing poses (Warrior I and II, Crescent Lunge, Downward Dog, and Tree), cool down, and rest and relaxation</td><td>13</td><td>70.5 ± 8.7</td><td>2 [2; 3]</td><td>-</td><td rowspan="2">12</td></tr><tr><td>-</td><td>13</td><td>65.0 ± 8.7</td><td>2 [2; 3]</td><td>-</td></tr><tr><td rowspan="2">Gandolfi et al., 2019</td><td rowspan="2">Comparator (control)</td><td rowspan="2">Usual daily routines</td><td rowspan="2">Trunk-specific rehabilitation</td><td rowspan="2">30 individual sessions of 60 min; 5 days a week for 4 weeks by PT</td><td>(1) Active self-correction exercises with visual feedback (i.e. mirror), with proprioceptive feedback (i.e. EMG feed-back), and without any feedback</td><td>19</td><td>72.4 ± 6.4</td><td>3 [1.5; 3]</td><td>8.01 ± 5.9</td><td rowspan="2">4 (+ follow-up 4)</td></tr><tr><td>(2) Trunk stabilization exercises (3) Functional tasks were used as the element of "distraction" (i.e. dual-task exercises) that engaged the patient's attention and induced them to maintain unconsciousness of the self-correction and trunk stabilization and reduce functional impairment</td><td>18</td><td>70.7 ± 6.6</td><td>2 [1.4; 3]</td><td>6.6 ± 4.3</td></tr><tr><td rowspan="2">Atan et al., 2019</td><td rowspan="2">Intervention</td><td rowspan="2">Body Weight Support Treadmill Training (BWSTT) with reduction of body weight of 20% 10% BWSTT</td><td rowspan="2">Active</td><td rowspan="2">30 individual sessions of 60 min; 5 days a week by PT</td><td>Joint mobilization, muscle strengthening and stretching, overground gait training and balance exercises</td><td>10</td><td>68.6 ± 8.2</td><td>2.6 ± 0.7</td><td>5.6 ± 5.3</td><td rowspan="2">6</td></tr><tr><td>Half a session for rehabilitation and the other half for BWSTT</td><td>10</td><td>72.2 ± 7.9</td><td>2.8 ± 0.6</td><td>9.8 ± 9.0</td></tr><tr><td></td><td>Comparator (sham)</td><td>0% BWSTT (patients are on the treadmill)</td><td></td><td></td><td></td><td>10</td><td>69.7 ± 8.0</td><td>2.7 ± 0.7</td><td>7.6 ± 6.4</td><td></td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>1</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td>Paolucci et al., 2017</td><td>Intervention</td><td>Meziere Rehabilitation</td><td>Active</td><td>10 sessions of 60 min; twice a week for 5 weeks by a PT trained for this technique</td><td>Three postures: (1) The patient was placed in the supine position; (2) The patient was placed in the supine position, with the upper limbs abducted to 120°; (3) The patient was placed in the supine position, with the lower extremities elevated at more than 90° of flexion of the hips and the knees extended or flexed, resting on a wall or supported by the PT, if the patient was unable to reach this position with the knees extended</td><td>17</td><td>66.0 ± 18.5</td><td>1.5 ± 0.8 for all the sample without statistically significant differences between the two groups</td><td>3 ± 1.2</td><td>5 (+ follow-up 8)</td></tr><tr><td></td><td>Comparator (another intervention)</td><td>Home exercise</td><td>Active</td><td>1 educational session of 60 min and a booklet of exercises to do: 10 sessions of 60 min of exercises (twice a week for 5 weeks) at home + Each patient was contacted by telephone every 2 weeks to monitor his/her adherence to the rehabilitation program</td><td>Each exercise was proposed for three sets of ten repetitions with a rest period of at least two minutes between sets. Exercises were getting more difficult through the weeks</td><td>17</td><td>67.0 ± 11.0</td><td></td><td></td><td></td></tr><tr><td>Reuter et al., 2011</td><td>Intervention</td><td>Nordic Walking (NW)</td><td>Active</td><td>72 sessions of 70 min; three times a week for 24 weeks by NW instructors</td><td>One session per week was dedicated to practising NW technique, the other sessions focused on endurance training</td><td>30</td><td>62 ± 3.2</td><td>2.53 ± 0.5</td><td>64.1 ± 48.7</td><td>24</td></tr><tr><td></td><td></td><td>Walking</td><td></td><td></td><td>The training session consisted of technique training, endurance training and a cooling down. One session per week included walking uphill to improve muscle strength</td><td>30</td><td>63 ± 3.1</td><td>2.5 ± 0.5</td><td>71.9 ± 50.6</td><td></td></tr><tr><td></td><td>Comparator (another intervention)</td><td>Flexibility and relaxation</td><td>Active</td><td>72 sessions of 70 min; three times a week for 24 weeks by PT</td><td>The training focused on stretching, improving balance and range of movements. The flexibility and relaxation programme did not include aerobic exercises</td><td>30</td><td>62.1 ± 2.5</td><td>2.5 ± 0.5</td><td>62.3 ± 38.2</td><td></td></tr><tr><td>Schmitz-Hübsch et al., 2006</td><td>Intervention</td><td>Qigong</td><td>Active</td><td>16 sessions of 60 min; once a week in two courses of 8 weeks with an 8-week pause in between; by an experienced teacher</td><td>Three opening exercises, three exercises from the syllabus "Frolic of the crane," all eight exercises from the syllabus "The eight brocades (in sitting position)," and closing exercises</td><td>30</td><td>64 ± 8</td><td>-</td><td>6.0 ± 5.5</td><td>24 (+ follow-up 28)</td></tr><tr><td></td><td>Comparator (control)</td><td>Usual care</td><td></td><td>-</td><td>-</td><td>19</td><td>63 ± 8</td><td>-</td><td>5.6 ± 3.8</td><td></td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023), https://doi.org/10.1016/j.neurol.2023.04.010
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>1</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11">Exercises</td></tr><tr><td rowspan="2">Paolucci et al., 2017</td><td>Intervention</td><td>Meziere Rehabilitation</td><td>Active</td><td>10 sessions of 60 min; twice a week for 5 weeks by a PT trained for this technique</td><td>Three postures: (1) The patient was placed in the supine position; (2) The patient was placed in the supine position, with the upper limbs abducted to 120°; (3) The patient was placed in the supine position, with the lower extremities elevated at more than 90° of flexion of the hips and the knees extended or flexed, resting on a wall or supported by the PT, if the patient was unable to reach this position with the knees extended</td><td>17</td><td>66.0 ± 18.5</td><td>1.5 ± 0.8 for all the sample without statistically significant differences between the two groups</td><td>3 ± 1.2</td><td>5 (+ follow-up 8)</td></tr><tr><td>Comparator (another intervention)</td><td>Home exercise</td><td>Active</td><td>1 educational session of 60 min and a booklet of exercises to do: 10 sessions of 60 min of exercises (twice a week for 5 weeks) at home + Each patient was contacted by telephone every 2 weeks to monitor his/her adherence to the rehabilitation program</td><td>Each exercise was proposed for three sets of ten repetitions with a rest period of at least two minutes between sets. Exercises were getting more difficult through the weeks</td><td>17</td><td>67.0 ± 11.0</td><td></td><td></td><td></td></tr><tr><td rowspan="2">Reuter et al., 2011</td><td>Intervention</td><td>Nordic Walking (NW)</td><td>Active</td><td>72 sessions of 70 min; three times a week for 24 weeks by NW instructors</td><td>One session per week was dedicated to practising NW technique, the other sessions focused on endurance training</td><td>30</td><td>62 ± 3.2</td><td>2.53 ± 0.5</td><td>64.1 ± 48.7</td><td>24</td></tr><tr><td>Comparator (another intervention)</td><td>Walking</td><td>Active</td><td>72 sessions of 70 min; three times a week for 24 weeks by PT</td><td>The training session consisted of technique training, endurance training and a cooling down. One session per week included walking uphill to improve muscle strength</td><td>30</td><td>63 ± 3.1</td><td>2.5 ± 0.5</td><td>71.9 ± 50.6</td><td></td></tr><tr><td rowspan="2">Schmitz-Hübsch et al., 2006</td><td>Intervention</td><td>Flexibility and relaxation</td><td>Active</td><td>16 sessions of 60 min; once a week in two courses of 8 weeks with an 8-week pause in between; by an experienced teacher</td><td>The training focused on stretching, improving balance and range of movements. The flexibility and relaxation programme did not include aerobic exercises</td><td>30</td><td>62.1 ± 2.5</td><td>2.5 ± 0.5</td><td>62.3 ± 38.2</td><td></td></tr><tr><td>Comparator (control)</td><td>Usual care</td><td>Active</td><td>-</td><td>Three opening exercises, three exercises from the syllabus "Frolic of the crane," all eight exercises from the syllabus "The eight brocades (in sitting position)," and closing exercises</td><td>30</td><td>64 ± 8</td><td>-</td><td>6.0 ± 5.5</td><td>24 (+ follow-up 28)</td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td colspan="11"><strong>Balneotherapy</strong></td></tr><tr><td rowspan="2">Pérez-de la Cruz et al., 2017</td><td>Intervention</td><td>Ai Chi Aquatic physiotherapy</td><td>Active</td><td>20 group sessions of 45 min; twice a week for 10 weeks by PT expert on Ai Chi</td><td>The sessions were designed with a gradual increase in difficulty: warm up activity followed by 35 minutes dedicated to practicing the Ai Chi program at the end of the session there was a calming down activity</td><td>15</td><td>66.8 ± 5.3</td><td>2.8 ± 0.2</td><td>6.2 ± 2.5</td><td>10 (+ follow-up 4)</td></tr><tr><td>Comparator (sham)</td><td>Dry physiotherapy</td><td></td><td>20 group sessions of 45 min twice a week for 10 weeks</td><td>Functional exercises based on activities of daily living, balance exercises, facial muscle exercises, proprioceptive exercises, muscle relaxation and stretching. During each session, emphasis was placed on training the trunk and lower limbs with the goal of improving the overall posture</td><td>15</td><td>67.5 ± 9.9</td><td>2.7 ± 1.0</td><td>6.7 ± 3.2</td><td></td></tr><tr><td rowspan="2">Volpe et al., 2017</td><td>Intervention</td><td>Intensive physiotherapy in water</td><td>Active</td><td>40 sessions of 60 min; 5 days a week for 8 weeks by a trained PT</td><td>Warm up with relaxing exercises, exercises for postural realignment, cooling down and relaxation exercises</td><td>13</td><td>70.6 ± 7.8</td><td>2.6 ± 0.5</td><td>9 ± 7.0</td><td>8 (+ follow-up 8)</td></tr><tr><td>Comparator (sham)</td><td>Physiotherapy</td><td></td><td></td><td>Exercises designed for postural deformities as much as possible similar to those used in the hydrotherapy programme</td><td>11</td><td>70 ± 7.8</td><td>2.7 ± 0.5</td><td>9.4 ± 7.5</td><td></td></tr><tr><td rowspan="2">Pérez-de la Cruz et al., 2019</td><td>Intervention</td><td>Ai Chi Aquatic physiotherapy</td><td>Active</td><td>20 group sessions of 45 min twice a week by PT expert on Ai Chi</td><td>The sessions were designed with a gradual increase in difficulty: warm up activity followed by 35 minutes dedicated to practicing the Ai Chi program at the end of the session there was a calming down activity</td><td>15</td><td>64.4 ± 5.1</td><td>2.8 ± 0.2</td><td>7.1 ± 2.0</td><td>10 (+ follow-up 4)</td></tr><tr><td>Comparator (sham)</td><td>Dry physiotherapy</td><td></td><td>20 group sessions of 45 min twice a week by a PT</td><td>Functional exercises based on activities of daily living, balance exercises, facial muscle exercises, proprioceptive exercises, muscle relaxation and stretching. During each session, emphasis was placed on training the trunk and lower limbs with the goal of improving the overall posture</td><td>15</td><td>65.8 ± 8.9</td><td>2.8 ± 1.0</td><td>7.7 ± 3.0</td><td></td></tr><tr><td colspan="11"><strong>Manual therapy</strong></td></tr><tr><td rowspan="2">Miyahara et al., 2018</td><td>Intervention</td><td>Therapeutic Thai Massage (TTM)</td><td>Passive</td><td>6 individual sessions of 30 min for 3 weeks by certified TTM practitioner</td><td>Kneading and pressing with moderate intensity, within patient's range of comfort, along six designated 'Sen' lines of the upper limbs (inner and outer arm)</td><td>30</td><td>66.4 ± 7.3</td><td>2.1 ± 0.3</td><td>8.5 ± 4.7</td><td>3</td></tr><tr><td>Comparator (control)</td><td>Usual medical care</td><td></td><td>-</td><td>-</td><td>30</td><td>64.1 ± 10.8</td><td>2.3 ± 0.5</td><td>9.2 ± 7.8</td><td></td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023). https://doi.org/10.1016/j.neurol.2023.04.010
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td colspan="11"><strong>Balneotherapy</strong></td></tr><tr><td rowspan="2">Pérez-de la Cruz et al., 2017</td><td>Intervention</td><td>Ai Chi Aquatic physiotherapy</td><td>Active</td><td>20 group sessions of 45 min; twice a week for 10 weeks by PT expert on Ai Chi</td><td>The sessions were designed with a gradual increase in difficulty: warm up activity followed by 35 minutes dedicated to practicing the Ai Chi program at the end of the session there was a calming down activity</td><td>15</td><td>66.8 ± 5.3</td><td>2.8 ± 0.2</td><td>6.2 ± 2.5</td><td>10 (+ follow-up 4)</td></tr><tr><td>Comparator (sham)</td><td>Dry physiotherapy</td><td>Active</td><td>20 group sessions of 45 min twice a week for 10 weeks</td><td>Functional exercises based on activities of daily living, balance exercises, facial muscle exercises, proprioceptive exercises, muscle relaxation and stretching. During each session, emphasis was placed on training the trunk and lower limbs with the goal of improving the overall posture</td><td>15</td><td>67.5 ± 9.9</td><td>2.7 ± 1.0</td><td>6.7 ± 3.2</td><td></td></tr><tr><td rowspan="2">Volpe et al., 2017</td><td>Intervention</td><td>Intensive physiotherapy in water</td><td>Active</td><td>40 sessions of 60 min; 5 days a week for 8 weeks by a trained PT</td><td>Warm up with relaxing exercises, exercises for postural realignment, cooling down and relaxation exercises</td><td>13</td><td>70.6 ± 7.8</td><td>2.6 ± 0.5</td><td>9 ± 7.0</td><td>8 (+ follow-up 8)</td></tr><tr><td>Comparator (sham)</td><td>Physiotherapy</td><td>Active</td><td></td><td>Exercises designed for postural deformities as much as possible similar to those used in the hydrotherapy programme</td><td>11</td><td>70 ± 7.8</td><td>2.7 ± 0.5</td><td>9.4 ± 7.5</td><td></td></tr><tr><td rowspan="2">Pérez-de la Cruz et al., 2019</td><td>Intervention</td><td>Ai Chi Aquatic physiotherapy</td><td>Active</td><td>20 group sessions of 45 min twice a week by PT expert on Ai Chi</td><td>The sessions were designed with a gradual increase in difficulty: warm up activity followed by 35 minutes dedicated to practicing the Ai Chi program at the end of the session there was a calming down activity</td><td>15</td><td>64.4 ± 5.1</td><td>2.8 ± 0.2</td><td>7.1 ± 2.0</td><td>10 (+ follow-up 4)</td></tr><tr><td>Comparator (sham)</td><td>Dry physiotherapy</td><td>Active</td><td>20 group sessions of 45 min twice a week by a PT</td><td>Functional exercises based on activities of daily living, balance exercises, facial muscle exercises, proprioceptive exercises, muscle relaxation and stretching. During each session, emphasis was placed on training the trunk and lower limbs with the goal of improving the overall posture</td><td>15</td><td>65.8 ± 8.9</td><td>2.8 ± 1.0</td><td>7.7 ± 3.0</td><td></td></tr><tr><td colspan="11"><strong>Manual therapy</strong></td></tr><tr><td rowspan="2">Miyahara et al., 2018</td><td>Intervention</td><td>Therapeutic Thai Massage (TTM)</td><td>Passive</td><td>6 individual sessions of 30 min for 3 weeks by certified TTM practitioner</td><td>Kneading and pressing with moderate intensity, within patient's range of comfort, along six designated 'Sen' lines of the upper limbs (inner and outer arm)</td><td>30</td><td>66.4 ± 7.3</td><td>2.1 ± 0.3</td><td>8.5 ± 4.7</td><td>3</td></tr><tr><td>Comparator (control)</td><td>Usual medical care</td><td>Active</td><td>-</td><td>-</td><td>30</td><td>64.1 ± 10.8</td><td>2.3 ± 0.5</td><td>9.2 ± 7.8</td><td></td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023). https://doi.org/10.1016/j.neurol.2023.04.010
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td rowspan="2">Skogar et al., 2013</td><td>Intervention</td><td>Tactile Touch (TT) and music</td><td>Passive</td><td>10 individual interventions of 60 min; twice per week for 3 weeks and then once a week for 4 weeks. Interventions were made by licensed massage therapists</td><td>Tactile touch corresponded of stroking with intention, using soft and encompassing hands on the skin. The strokes were given with respect, empathy and sensitivity regarding the special needs of the individual. 1. Back of legs 2. The back 3. Back of the head The recipient turns over 4. Abdomen 5. Chest 6. Face, ears 7. Front of head 8. Right arm, then right hand 9. Left arm, then left hand 10. Left leg, then left foot 11. Right leg, then right foot</td><td>29</td><td>Male [50; 78] &amp; Female [60; 79]</td><td>Median [10th/90th percentile]: Male 1.5 [1.0/2.5] &amp; Female 2.5 [1.5/ 3.0]</td><td>-</td><td>7 (+ follow-up 26)</td></tr><tr><td>Comparator (control)</td><td>Rest To Music (RTM)</td><td></td><td>10 interventions of 60 min</td><td>The music was identical for TT and RTM: "Music for well-being II - Letting go of stress", LC6607 F6nix Music II, Sweden. All patients were asked to indicate the most comfortable volume before the intervention</td><td>15-</td><td>Male [50; 74] &amp; Female [50; 74]</td><td>Median [10th/90th percentile]: Male 3.0 [1.5/3.0] &amp; Female 2.0 [1.0/ 4.0]</td><td>-</td><td></td></tr><tr><td colspan="11"><strong>Acupuncture</strong></td></tr><tr><td rowspan="2">Lei et al., 2016</td><td>Intervention</td><td>Electro-acupuncture (EA)</td><td>Passive</td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>All the EA points were stimulated at the same time with frequency of 100 Hz or 4 Hz. Eleven points were selected: Foot motor Sensory Area, Balance Area, GV 20, GV 14, LI4, GB34, BL40, SP6, KI3, LR3</td><td>10</td><td>69.8 ± 4.5</td><td>3.0 ± 1.0</td><td>6.2 ± 5.9</td><td>3</td></tr><tr><td>Comparator (sham)</td><td>Sham EA</td><td></td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>The Sham EA was performed for the control group with insertion of needles less than 4 mm, just under the skin at non-acupuncture points The electric stimulation in sham EA was performed in a similar fashion to the real EA but with intensity equal to zero</td><td>5</td><td>71.0 ± 11.7</td><td>2.9 ± 0.7</td><td>5.2 ± 4.7</td><td></td></tr><tr><td rowspan="2">Toosizadeh et al., 2015</td><td>Intervention</td><td>EA</td><td>Passive</td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>All the EA points were stimulated at the same time with frequency of 100 Hz or 4 Hz. Eleven points were selected: Foot motor Sensory Area, Balance Area, GV 20, GV 14, LI4, GB34, BL40, SP6, KI3, LR3</td><td>10</td><td>71.2 ± 6.3</td><td>-</td><td>3.0 ± 1.0</td><td>3</td></tr><tr><td>Comparator (sham)</td><td>Sham EA</td><td></td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>The Sham EA was performed for the control group with insertion of needles less than 4 mm, just under the skin at non-acupuncture points The electric stimulation in sham EA was performed in a similar fashion to the real EA but with intensity equal to zero</td><td>5</td><td>74.6 ± 6.5</td><td>-</td><td>2.9 ± 0.7</td><td></td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td rowspan="2">Skogar et al., 2013</td><td>Intervention</td><td>Tactile Touch (TT) and music</td><td>Passive</td><td>10 individual interventions of 60 min; twice per week for 3 weeks and then once a week for 4 weeks. Interventions were made by licensed massage therapists</td><td>Tactile touch corresponded of stroking with intention, using soft and encompassing hands on the skin. The strokes were given with respect, empathy and sensitivity regarding the special needs of the individual. 1. Back of legs 2. The back 3. Back of the head The recipient turns over 4. Abdomen 5. Chest 6. Face, ears 7. Front of head 8. Right arm, then right hand 9. Left arm, then left hand 10. Left leg, then left foot 11. Right leg, then right foot</td><td>29</td><td>Male [50; 78] &amp; Female [60; 79]</td><td>Median [10th/90th percentile]: Male 1.5 [1.0/2.5] &amp; Female 2.5 [1.5/ 3.0]</td><td>-</td><td>7 (+ follow-up 26)</td></tr><tr><td>Comparator (control)</td><td>Rest To Music (RTM)</td><td></td><td>10 interventions of 60 min</td><td>The music was identical for TT and RTM: "Music for well-being II - Letting go of stress", LC6607 F6nix Music II, Sweden. All patients were asked to indicate the most comfortable volume before the intervention</td><td>15-</td><td>Male [50; 74] &amp; Female [50; 74]</td><td>Median [10th/90th percentile]: Male 3.0 [1.5/3.0] &amp; Female 2.0 [1.0/ 4.0]</td><td>-</td><td></td></tr><tr><td colspan="11"><strong>Acupuncture</strong></td></tr><tr><td rowspan="2">Lei et al., 2016</td><td>Intervention</td><td>Electro-acupuncture (EA)</td><td>Passive</td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>All the EA points were stimulated at the same time with frequency of 100 Hz or 4 Hz. Eleven points were selected: Foot motor Sensory Area, Balance Area, GV 20, GV 14, LI4, GB34, BL40, SP6, KI3, LR3</td><td>10</td><td>69.8 ± 4.5</td><td>3.0 ± 1.0</td><td>6.2 ± 5.9</td><td>3</td></tr><tr><td>Comparator (sham)</td><td>Sham EA</td><td></td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>The Sham EA was performed for the control group with insertion of needles less than 4 mm, just under the skin at non-acupuncture points The electric stimulation in sham EA was performed in a similar fashion to the real EA but with intensity equal to zero</td><td>5</td><td>71.0 ± 11.7</td><td>2.9 ± 0.7</td><td>5.2 ± 4.7</td><td></td></tr><tr><td rowspan="2">Toosizadeh et al., 2015</td><td>Intervention</td><td>EA</td><td>Passive</td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>All the EA points were stimulated at the same time with frequency of 100 Hz or 4 Hz. Eleven points were selected: Foot motor Sensory Area, Balance Area, GV 20, GV 14, LI4, GB34, BL40, SP6, KI3, LR3</td><td>10</td><td>71.2 ± 6.3</td><td>-</td><td>3.0 ± 1.0</td><td>3</td></tr><tr><td>Comparator (sham)</td><td>Sham EA</td><td></td><td>3 sessions of 30 min in 3 weeks by a physician who had more than 5 years of experience in acupuncture and was certified</td><td>The Sham EA was performed for the control group with insertion of needles less than 4 mm, just under the skin at non-acupuncture points The electric stimulation in sham EA was performed in a similar fashion to the real EA but with intensity equal to zero</td><td>5</td><td>74.6 ± 6.5</td><td>-</td><td>2.9 ± 0.7</td><td></td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&amp;Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11">Exercises</td></tr><tr><td colspan="11">Botanical preparation</td></tr><tr><td rowspan="2">Chua et al., 2017</td><td>Intervention</td><td>Active herbal treatment Jiawei Liujunzi Tang (JLT)</td><td>Passive</td><td rowspan="2">2 doses per day, 11 g each time (a dosage equivalent to 55 g of herbs)</td><td rowspan="2">Patients were instructed to take the granules orally, at least two hours apart from taking any routine Western medication</td><td>45</td><td>63.5 ± 9.7</td><td>2.1 ± 0.6</td><td>6.4 ± 4.2</td><td rowspan="2">32 (+ follow-up 6)</td></tr><tr><td>Comparator (sham)</td><td>Placebo pill</td><td></td><td>Composition of the placebo pill: caramel, gardenia yellow pigment, sunset yellow, permicol egg yellow, cocoa brown, citric acid, sodium cyclamate, dextrin, and broadleaf holly leaf; with the same instruction as the intervention group</td><td>46</td><td>63.3 ± 8.2</td><td>2.0 ± 0.6</td><td>5.4 ± 3.8</td></tr><tr><td rowspan="2">Carroll et al., 2004</td><td>Intervention</td><td>Active cannador capsule</td><td>Passive</td><td rowspan="2">Medication was taken twice daily for 10 weeks. The dose of cannabis extract or placebo administered was based on body weight, with a maximum possible dose of 0.25 mg/kg of THC per day</td><td rowspan="2">Capsules of cannador, an ethanolic extract of Cannabis sativa standardized to 2.5 mg of 9-THC and 1.25 mg of cannabidiol per capsule</td><td>9</td><td>67 [51; 78]</td><td>3.0 [2.5; 4]</td><td>14 [4; 32]</td><td rowspan="2">10</td></tr><tr><td>Comparator (sham)</td><td>Placebo pill</td><td></td><td>Synthetic oil vehicle</td><td>8</td><td></td><td></td><td></td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023). https://doi.org/10.1016/j.neurol.2023.04.010
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&amp;Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11">Exercises</td></tr><tr><td colspan="11">Botanical preparation</td></tr><tr><td rowspan="2">Chua et al., 2017</td><td>Intervention</td><td>Active herbal treatment Jiawei Liujunzi Tang (JLT)</td><td>Passive</td><td>2 doses per day, 11 g each time (a dosage equivalent to 55 g of herbs)</td><td>Patients were instructed to take the granules orally, at least two hours apart from taking any routine Western medication</td><td>45</td><td>63.5 ± 9.7</td><td>2.1 ± 0.6</td><td>6.4 ± 4.2</td><td rowspan="2">32 (+ follow-up 6)</td></tr><tr><td>Comparator (sham)</td><td>Placebo pill</td><td></td><td></td><td>Composition of the placebo pill: caramel, gardenia yellow pigment, sunset yellow, permicol egg yellow, cocoa brown, citric acid, sodium cyclamate, dextrin, and broadleaf holly leaf; with the same instruction as the intervention group</td><td>46</td><td>63.3 ± 8.2</td><td>2.0 ± 0.6</td><td>5.4 ± 3.8</td></tr><tr><td rowspan="2">Carroll et al., 2004</td><td>Intervention</td><td>Active cannador capsule</td><td>Passive</td><td>Medication was taken twice daily for 10 weeks. The dose of cannabis extract or placebo administered was based on body weight, with a maximum possible dose of 0.25 mg/kg of THC per day</td><td>Capsules of cannador, an ethanolic extract of Cannabis sativa standardized to 2.5 mg of 9-THC and 1.25 mg of cannabidiol per capsule</td><td>9</td><td>67 [51; 78]</td><td>3.0 [2.5; 4]</td><td>14 [4; 32]</td><td rowspan="2">10</td></tr><tr><td>Comparator (sham)</td><td>Placebo pill</td><td></td><td>Medication was taken twice daily for 10 weeks</td><td>Synthetic oil vehicle</td><td>8</td><td></td><td></td><td></td></tr></tbody></table>

Please cite this article in press as: Huissoud M, et al. The effectiveness and safety of non-pharmacological intervention for pain management in Parkinson's disease: A systematic review. Revue neurologique (2023). https://doi.org/10.1016/j.neurol.2023.04.010
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td colspan="11"><strong>Body-psychological practice</strong></td></tr><tr><td>Pickut et al., 2015</td><td>Intervention</td><td>Mind-Based Intervention</td><td>Active</td><td>8 sessions of 150 min meetings on 8 consecutive weeks without the one-time full-day session in the sixth week of practice by two experienced mindfulness teachers</td><td>Audio recordings containing 45 min guided mindfulness exercises (meditation, yoga, and the body scan) were given with instructions for daily home practice corresponding to the course sequence. Time spent in mindfulness practices, as reported by the participants, was recorded weekly for each participant</td><td>14</td><td>61.4 ± 11.3</td><td>2.1 ± 0.3</td><td>-</td><td>8</td></tr><tr><td></td><td>Comparator (control)</td><td>Usual care</td><td></td><td>-</td><td>-</td><td>13</td><td>62.2 ± 6.6</td><td>2.2 ± 0.5</td><td>-</td><td></td></tr><tr><td colspan="11"><strong>Electromagnetic methods</strong></td></tr><tr><td>Li et al., 2020</td><td>Intervention</td><td>High-frequency repetitive Transcranial Magnetic Stimulation (HF rTMS)</td><td>Passive</td><td>5 consecutive daily sessions of 20 min</td><td>The investigators used a handheld 7-cm figure- 8 coil. The coil was centered over the scalp above the hand area of the M1 contralateral to where the participant reported feeling pain. If the patient reported bilateral or diffuse pain, then the coil was placed over the left M1. The coil was oriented at a 45° angle relative to the midsagittal plane<br>The rTMS protocol involved applying a train of 100 rTMS pulses at 20 Hz once per minute for 20 min. Each train's intensity was set at 80% of the participant's resting motor threshold</td><td>24</td><td>61.7 ± 6.9</td><td>1.9 ± 0.6</td><td>5.5 ± 3.7</td><td>1 (+ follow-up 4)</td></tr><tr><td></td><td>Comparator (sham)</td><td>Sham HF rTMS</td><td></td><td></td><td>The sham protocol was similar to the rTMS protocol, but the coil was oriented at a 90° angle relative to the midsagittal plane to partly reproduce the subjective sensations associated with rTMS while not inducing currents within the brain</td><td>24</td><td>61.5 ± 8.4</td><td>1.8 ± 0.6</td><td>6.5 ± 5.2</td><td></td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td colspan="11"><strong>Body-psychological practice</strong></td></tr><tr><td>Pickut et al., 2015</td><td>Intervention</td><td>Mind-Based Intervention</td><td>Active</td><td>8 sessions of 150 min meetings on 8 consecutive weeks without the one-time full-day session in the sixth week of practice by two experienced mindfulness teachers</td><td>Audio recordings containing 45 min guided mindfulness exercises (meditation, yoga, and the body scan) were given with instructions for daily home practice corresponding to the course sequence. Time spent in mindfulness practices, as reported by the participants, was recorded weekly for each participant</td><td>14</td><td>61.4 ± 11.3</td><td>2.1 ± 0.3</td><td>-</td><td>8</td></tr><tr><td></td><td>Comparator (control)</td><td>Usual care</td><td></td><td>-</td><td>-</td><td>13</td><td>62.2 ± 6.6</td><td>2.2 ± 0.5</td><td>-</td><td></td></tr><tr><td colspan="11"><strong>Electromagnetic methods</strong></td></tr><tr><td>Li et al., 2020</td><td>Intervention</td><td>High-frequency repetitive Transcranial Magnetic Stimulation (HF rTMS)</td><td>Passive</td><td>5 consecutive daily sessions of 20 min</td><td>The investigators used a handheld 7-cm figure- 8 coil. The coil was centered over the scalp above the hand area of the M1 contralateral to where the participant reported feeling pain. If the patient reported bilateral or diffuse pain, then the coil was placed over the left M1. The coil was oriented at a 45° angle relative to the midsagittal plane<br>The rTMS protocol involved applying a train of 100 rTMS pulses at 20 Hz once per minute for 20 min. Each train's intensity was set at 80% of the participant's resting motor threshold</td><td>24</td><td>61.7 ± 6.9</td><td>1.9 ± 0.6</td><td>5.5 ± 3.7</td><td>1 (+ follow-up 4)</td></tr><tr><td></td><td>Comparator (sham)</td><td>Sham HF rTMS</td><td></td><td></td><td>The sham protocol was similar to the rTMS protocol, but the coil was oriented at a 90° angle relative to the midsagittal plane to partly reproduce the subjective sensations associated with rTMS while not inducing currents within the brain</td><td>24</td><td>61.5 ± 8.4</td><td>1.8 ± 0.6</td><td>6.5 ± 5.2</td><td></td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11">Exercises</td></tr><tr><td colspan="11">Multi-professional care</td></tr><tr><td rowspan="2">Gage et al., 2014</td><td rowspan="2">Intervention</td><td>Specialist rehabilitation intervention: Multidisciplinary Team care (MDT)</td><td>Active &amp; passive</td><td>The rehabilitation intervention was coordinated by the Parkinson's nurse specialist, and involved specialist input from each professional, over a period of six weeks. The team met face-to-face four times in each six-week cycle to discuss patients' plans and progress, and communicated by email and telephone at other times. Two hospital consultants (neurologist and geriatrician), both with a special interest in movement disorders, could be called upon by the MDT for medication changes or advice</td><td>90</td><td>72.9 ± 8.6</td><td>2.4</td><td>-</td><td>6 (+ follow-up 30)</td><td></td></tr><tr><td>MDT + Ongoing support</td><td></td><td>About one hour per week per patient was allowed for ongoing support, and contact was through a mix of home visits and telephone, through which the care assistant monitored progress in implementation of the agreed care plan and reported back to the MDT</td><td>90</td><td>74.0 ± 8.2</td><td>2.4</td><td>-</td><td>24 (+ follow-up 12)</td><td></td></tr><tr><td>Comparator (control)</td><td>Usual care</td><td></td><td>No coordinated team care planning or ongoing support</td><td>90</td><td>71.6 ± 7.9</td><td>2.2</td><td>-</td><td>6 (+ follow-up 30)</td><td></td></tr></tbody></table>

PT: physiotherapist; H&Y: Hoehn and Yahr; 'Sen' lines correspond to energy lines, in the traditional Thai massage.

<footnote><sup>a</sup> Groups are defined as the Intervention group or the Comparator group. For the comparator group, "control" corresponds to a comparison without any standard intervention or treatment (that is usual routine care); "sham" is defined as an intervention with the same time and type of interaction with the patient but without a supposed specific effect; and "another intervention" stands for another intervention modality (e.g. another medication, therapeutic education, physical activity program etc.).</footnote>
<table><caption>Table 2 (Continued)</caption><thead><tr><th>Authors</th><th>Group<sup>a</sup></th><th>Name of intervention</th><th>Active or passive intervention</th><th>Planning of intervention</th><th>Description of intervention</th><th>Sample size by group (n)</th><th>Age (year) mean ± SD; [Range]</th><th>H&Y mean ± SD; [Range]</th><th>Disease duration (year) mean ± SD; [Range]</th><th>Study duration (weeks)</th></tr></thead><tbody><tr><td colspan="11"><strong>Exercises</strong></td></tr><tr><td colspan="11"><strong>Multi-professional care</strong></td></tr><tr><td rowspan="2">Gage et al., 2014</td><td rowspan="2">Intervention</td><td>Specialist rehabilitation intervention: Multidisciplinary Team care (MDT)</td><td>Active &amp; passive</td><td>The rehabilitation intervention was coordinated by the Parkinson's nurse specialist, and involved specialist input from each professional, over a period of six weeks. The team met face-to-face four times in each six-week cycle to discuss patients' plans and progress, and communicated by email and telephone at other times. Two hospital consultants (neurologist and geriatrician), both with a special interest in movement disorders, could be called upon by the MDT for medication changes or advice</td><td>90</td><td>72.9 ± 8.6</td><td>2.4</td><td>-</td><td>6 (+ follow-up 30)</td><td></td></tr><tr><td>MDT + Ongoing support</td><td></td><td>About one hour per week per patient was allowed for ongoing support, and contact was through a mix of home visits and telephone, through which the care assistant monitored progress in implementation of the agreed care plan and reported back to the MDT</td><td>90</td><td>74.0 ± 8.2</td><td>2.4</td><td>-</td><td>24 (+ follow-up 12)</td><td></td></tr><tr><td>Comparator (control)</td><td>Usual care</td><td></td><td>No coordinated team care planning or ongoing support</td><td>90</td><td>71.6 ± 7.9</td><td>2.2</td><td>-</td><td></td><td>6 (+ follow-up 30)</td><td></td></tr></tbody></table>

PT: physiotherapist; H&Y: Hoehn and Yahr; 'Sen' lines correspond to energy lines, in the traditional Thai massage.

<footnote><sup>a</sup> Groups are defined as the Intervention group or the Comparator group. For the comparator group, "control" corresponds to a comparison without any standard intervention or treatment (that is usual routine care); "sham" is defined as an intervention with the same time and type of interaction with the patient but without a supposed specific effect; and "another intervention" stands for another intervention modality (e.g. another medication, therapeutic education, physical activity program etc.).</footnote>
<table><caption>Table 3 – NPIs and management of pain.</caption><thead><tr><th>Authors</th><th>Intervention</th><th>Blind</th><th>Evaluation of pain</th><th>Assessment in ON or OFF<sup>a</sup> state</th><th>TIDIER list completion</th><th>Adverse event (AE)</th><th>Results</th></tr></thead><tbody><tr><td colspan="8">Exercises</td></tr><tr><td>Schaible et al., 2021</td><td>Lee Silverman Voice Treatment (LSVT)-BIG training</td><td>Open</td><td>Miscellany subscale of the Non-Motor Symptom Scale (NMSS)</td><td>ON</td><td>8/8</td><td>None</td><td>Only the INTENSIVE group had a significant different change in NMSS total compared to the Regular physiotherapy group (P = 0.03) and a significant amelioration of NMSS miscellany subscore (P = 0.036) after 8 weeks, but between groups changes were not significant (P = 0.593)</td></tr><tr><td>Myers et al., 2020</td><td>Intensive physiotherapy with an individual training plan Regular physiotherapy Vinyasa Yoga</td><td>Open</td><td>Revised Oswestry Disability Index (RODI)</td><td>ON</td><td>7/8</td><td>-</td><td>No intergroup statistic. Decrease of pain only in the yoga group (P = 0.03)</td></tr><tr><td>Gandolfi et al., 2019</td><td>Usual daily routines Trunk-specific rehabilitation</td><td>Single-blind (assessor)</td><td>Numeric Rating Scale (NRS)</td><td>ON</td><td>7/8</td><td>None</td><td>No significant differences between the two groups from T0<sup>a</sup> and T1 (P = 0.87) and from T0 and T2 (P = 0.25). Significant reduction of pain in both groups from T0 to T2 intervention group: P = 0.001; Control Group: P &lt; 0.001</td></tr><tr><td>Atan et al., 2019</td><td>Passive mobilisation Body Weight Support Treadmill Training (BWSTT) with reduction of body weight of 20% 10% BWSTT 0% BWSTT</td><td>Double-blind (assessor & patients)</td><td>Nottingham Health Profile (NHP) Pain subscore</td><td>ON</td><td>8/8</td><td>Few adverse events such as muscle or joint pain</td><td>Decrease of pain only in the intervention groups (10% or 20% BWSTT) while pain increased in the control group (P &lt; 0.05) with an intergroup effect (P = 0.013)</td></tr><tr><td>Paolucci et al., 2017</td><td>Meziere Rehabilitation</td><td>Single-blind (assessor)</td><td>Visual Analog Scale (VAS)</td><td>ON</td><td>7/8</td><td>None</td><td>No significant intergroup differences (P = 0.2 at T1<sup>a</sup> and P = 0.8 at T2). Significant improvement of pain only in the intervention group (P &lt; 0.001)</td></tr><tr><td>Reuter et al., 2011</td><td>Home exercise Nordic Walking (NW)</td><td>Single-blind (assessor)</td><td>VAS for several regions of the body</td><td>-</td><td>7/8</td><td>Cardiovascular side effects (hypotension and injuries, caused by fall or overuse)</td><td>Reduction of pain of the neck, the hip and the sacroiliac joint in all groups; while higher amelioration of pain in the back (P &lt; 0.001), hands (P &lt; 0.001) and legs (P &lt; 0.002) for both Walking groups in comparison with control group. In the Nordic walking group up to 30% of patients became free of pain after the training</td></tr><tr><td>Schmitz-Hübsch et al., 2006</td><td>Walking Flexibility and relaxation Qigong</td><td>Open</td><td>Semi-structured interviews & consumption of antalgic drugs</td><td>ON</td><td>7/8</td><td>-</td><td>No intergroup statistic realised. No significant differences within groups, even if pain complaints tended to reduce only in the treatment group</td></tr><tr><td colspan="8">Usual care</td></tr></tbody></table>
<table><caption>Table 3 – NPIs and management of pain.</caption><thead><tr><th>Authors</th><th>Intervention</th><th>Blind</th><th>Evaluation of pain</th><th>Assessment in ON or OFF<sup>a</sup> state</th><th>TiDIER list completion</th><th>Adverse event (AE)</th><th>Results</th></tr></thead><tbody><tr><td colspan="8">Exercises</td></tr><tr><td>Schaible et al., 2021</td><td>Lee Silverman Voice Treatment (LSVT)-BIG training</td><td>Open</td><td>Miscellany subscale of the Non-Motor Symptom Scale (NMSS)</td><td>ON</td><td>8/8</td><td>None</td><td>Only the INTENSIVE group had a significant different change in NMSS total compared to the Regular physiotherapy group (P = 0.03) and a significant amelioration of NMSS miscellany subscore (P = 0.036) after 8 weeks, but between groups changes were not significant (P = 0.593)</td></tr><tr><td>Myers et al., 2020</td><td>Intensive physiotherapy with an individual training plan</td><td>Open</td><td>Revised Oswestry Disability Index (RODI)</td><td>ON</td><td>7/8</td><td>-</td><td>No intergroup statistic. Decrease of pain only in the yoga group (P = 0.03)</td></tr><tr><td>Gandolfi et al., 2019</td><td>Regular physiotherapy</td><td>Open</td><td>Numeric Rating Scale (NRS)</td><td>ON</td><td>7/8</td><td>None</td><td>No significant differences between the two groups from T0<sup>a</sup> and T1 (P = 0.87) and from T0 and T2 (P = 0.25). Significant reduction of pain in both groups from T0 to T2 intervention group: P = 0.001; Control Group: P &lt; 0.001</td></tr><tr><td>Atan et al., 2019</td><td>Passive mobilisation</td><td>Double-blind (assessor & patients)</td><td>Nottingham Health Profile (NHP) Pain subscore</td><td>ON</td><td>8/8</td><td>Few adverse events such as muscle or joint pain</td><td>Decrease of pain only in the intervention groups (10% or 20% BWSTT) while pain increased in the control group (P &lt; 0.05) with an intergroup effect (P = 0.013)</td></tr><tr><td>Paolucci et al., 2017</td><td>Body Weight Support Treadmill Training (BWSTT) with reduction of body weight of 20% 10% BWSTT</td><td>Single-blind (assessor)</td><td>Visual Analog Scale (VAS)</td><td>ON</td><td>7/8</td><td>None</td><td>No significant intergroup differences (P = 0.2 at T1<sup>a</sup> and P = 0.8 at T2). Significant improvement of pain only in the intervention group (P &lt; 0.001)</td></tr><tr><td>Reuter et al., 2011</td><td>Meziere Rehabilitation</td><td>Single-blind (assessor)</td><td>VAS for several regions of the body</td><td>-</td><td>7/8</td><td>Cardiovascular side effects (hypotension and injuries, caused by fall or overuse)</td><td>Reduction of pain of the neck, the hip and the sacroiliac joint in all groups; while higher amelioration of pain in the back (P &lt; 0.001), hands (P &lt; 0.001) and legs (P &lt; 0.002) for both Walking groups in comparison with control group. In the Nordic walking group up to 30% of patients became free of pain after the training</td></tr><tr><td>Schmitz-Hübsch et al., 2006</td><td>Home exercise</td><td>Open</td><td>Semi-structured interviews & consumption of antalgic drugs</td><td>ON</td><td>7/8</td><td>-</td><td>No intergroup statistic realised. No significant differences within groups, even if pain complaints tended to reduce only in the treatment group</td></tr><tr><td></td><td>Walking Flexibility and relaxation</td><td>Open</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td>Qigong</td><td>Open</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td>Usual care</td><td>Open</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><caption>Table 3 (Continued)</caption><thead><tr><th>Authors</th><th>Intervention</th><th>Blind</th><th>Evaluation of pain</th><th>Assessment in ON or OFF* state</th><th>TiDIER list completion</th><th>Adverse event (AE)</th><th>Results</th></tr></thead><tbody><tr><td colspan="8">Exercises</td></tr><tr><td colspan="8">Balneotherapy</td></tr><tr><td>Pérez-de la Cruz et al., 2017</td><td>Ai Chi Aquatic Physiotherapy</td><td>Single-blind (assessor)</td><td>VAS (Primary Outcome)</td><td>OFF</td><td>8/8</td><td>None</td><td>No intergroup statistic presented. Improvement in each group on the VAS pain scale (treatment × time interaction effect P = 0.005)</td></tr><tr><td>Volpe et al., 2017</td><td>Dry physiotherapy<br>Intensive physiotherapy in water<br>Physiotherapy</td><td>Single-blind (assessor)</td><td>VAS</td><td>ON</td><td>6/8</td><td>Orthostatic hypotension, pulmonary disease</td><td>No significant differences between groups. No intragroup statistic realised</td></tr><tr><td>Pérez-de la Cruz et al., 2019</td><td>Ai Chi Aquatic Physiotherapy<br>Dry physiotherapy</td><td>Single-blind (assessor)</td><td>VAS</td><td>OFF</td><td>7/8</td><td>None</td><td>No intergroup statistic presented. Improvement in each group on the VAS pain scale (treatment × time interaction effect P = 0.005)</td></tr><tr><td colspan="8">Manual therapy</td></tr><tr><td>Miyahara et al., 2018</td><td>Therapeutic Thai Massage (TTM)</td><td>Single-blind (assessor)</td><td>VAS</td><td>ON</td><td>7/8</td><td>None</td><td>Intergroup statistics showed an improvement of pain with a significant effect of the intervention group (P &lt; 0.001)</td></tr><tr><td>Skogar et al., 2013</td><td>Usual medical care<br>Tactile Touch (TT) and music</td><td>Open</td><td>Patient's Evaluation Analysis (PEA), VAS of maximum pain, Pain-O-Meter (POM) (Primary Outcome)</td><td>-</td><td>8/8</td><td>-</td><td>There were no significant differences of pain evolution between groups. Only at short-term (week 3), emotional and physical expression of pain improved significantly only in the TT group (P = 0.03)</td></tr><tr><td colspan="8">Acupuncture</td></tr><tr><td>Lei et al., 2016</td><td>Electro-acupuncture (EA)<br>Sham EA</td><td>Double-blind (assessor & patients)</td><td>VAS</td><td>OFF</td><td>7/8</td><td>Transient light-headedness</td><td>No intergroup statistic realised. No significant pain improvement (P = 0.26 in the EA group)</td></tr><tr><td>Toosizadeh et al., 2015</td><td>EA<br>Sham EA</td><td>Double-blind (assessor & patients)</td><td>VAS</td><td>OFF</td><td>7/8</td><td>Transient light-headedness</td><td>No intergroup statistic realised. Reduction of VAS in both groups but changes were not significant (P = 0.26 in the EA group)</td></tr><tr><td colspan="8">Botanical preparation</td></tr><tr><td>Chua et al., 2017</td><td>Active herbal treatment Jiawei Liujunzi Tang (JLT) Placebo pill</td><td>Double-blind (assessor & patients)</td><td>MDS-UPDRS I - question 9 about pain</td><td>ON</td><td>8/8</td><td>Abdominal pain, dyspepsia, diarrhoea, dizziness, back pain and joint pain</td><td>No significant differences between groups (P = 0.3). No intragroup statistic realised</td></tr><tr><td>Carroll et al., 2004</td><td>Active cannador capsule<br>Placebo pill</td><td>Crossover study double-blind (assessor & patients)</td><td>McGill Pain Questionnaire (MPQ)</td><td>ON</td><td>8/8</td><td>A similar spectrum of adverse events was recorded in both treatment and placebo groups during the RCT, although more common in the treatment group (n = 37 vs. n = 15)</td><td>No significant differences between groups (P = 0.4). No intragroup statistic realised</td></tr></tbody></table>
<table><caption>Table 3 (Continued)</caption><thead><tr><th>Authors</th><th>Intervention</th><th>Blind</th><th>Evaluation of pain</th><th>Assessment in ON or OFF* state</th><th>TiDIER list completion</th><th>Adverse event (AE)</th><th>Results</th></tr></thead><tbody><tr><td colspan="8">Exercises</td></tr><tr><td colspan="8">Balneotherapy</td></tr><tr><td>Pérez-de la Cruz et al., 2017</td><td>Ai Chi Aquatic Physiotherapy</td><td>Single-blind (assessor)</td><td>VAS (Primary Outcome)</td><td>OFF</td><td>8/8</td><td>None</td><td>No intergroup statistic presented. Improvement in each group on the VAS pain scale (treatment × time interaction effect P = 0.005)</td></tr><tr><td>Volpe et al., 2017</td><td>Dry physiotherapy<br>Intensive physiotherapy in water<br>Physiotherapy</td><td>Single-blind (assessor)</td><td>VAS</td><td>ON</td><td>6/8</td><td>Orthostatic hypotension, pulmonary disease</td><td>No significant differences between groups. No intragroup statistic realised</td></tr><tr><td>Pérez-de la Cruz et al., 2019</td><td>Ai Chi Aquatic Physiotherapy<br>Dry physiotherapy</td><td>Single-blind (assessor)</td><td>VAS</td><td>OFF</td><td>7/8</td><td>None</td><td>No intergroup statistic presented. Improvement in each group on the VAS pain scale (treatment × time interaction effect P = 0.005)</td></tr><tr><td colspan="8">Manual therapy</td></tr><tr><td>Miyahara et al., 2018</td><td>Therapeutic Thai Massage (TTM)</td><td>Single-blind (assessor)</td><td>VAS</td><td>ON</td><td>7/8</td><td>None</td><td>Intergroup statistics showed an improvement of pain with a significant effect of the intervention group (P &lt; 0.001)</td></tr><tr><td>Skogar et al., 2013</td><td>Usual medical care<br>Tactile Touch (TT) and music</td><td>Open</td><td>Patient's Evaluation Analysis (PEA), VAS of maximum pain, Pain-O-Meter (POM) (Primary Outcome)</td><td>-</td><td>8/8</td><td>-</td><td>There were no significant differences of pain evolution between groups. Only at short-term (week 3), emotional and physical expression of pain improved significantly only in the TT group (P = 0.03)</td></tr><tr><td colspan="8">Acupuncture</td></tr><tr><td>Lei et al., 2016</td><td>Electro-acupuncture (EA)<br>Sham EA</td><td>Double-blind (assessor & patients)</td><td>VAS</td><td>OFF</td><td>7/8</td><td>Transient light-headedness</td><td>No intergroup statistic realised. No significant pain improvement (P = 0.26 in the EA group)</td></tr><tr><td>Toosizadeh et al., 2015</td><td>EA<br>Sham EA</td><td>Double-blind (assessor & patients)</td><td>VAS</td><td>OFF</td><td>7/8</td><td>Transient light-headedness</td><td>No intergroup statistic realised. Reduction of VAS in both groups but changes were not significant (P = 0.26 in the EA group)</td></tr><tr><td colspan="8">Botanical preparation</td></tr><tr><td>Chua et al., 2017</td><td>Active herbal treatment Jiawei Liujunzi Tang (JLT) Placebo pill</td><td>Double-blind (assessor & patients)</td><td>MDS-UPDRS I – question 9 about pain</td><td>ON</td><td>8/8</td><td>Abdominal pain, dyspepsia, diarrhoea, dizziness, back pain and joint pain</td><td>No significant differences between groups (P = 0.3). No intragroup statistic realised</td></tr><tr><td>Carroll et al., 2004</td><td>Active cannador capsule<br>Placebo pill</td><td>Crossover study double-blind (assessor & patients)</td><td>McGill Pain Questionnaire (MPQ)</td><td>ON</td><td>8/8</td><td>A similar spectrum of adverse events was recorded in both treatment and placebo groups during the RCT, although more common in the treatment group (n = 37 vs. n = 15)</td><td>No significant differences between groups (P = 0.4). No intragroup statistic realised</td></tr></tbody></table>
<table><caption>Table 3 (Continued)</caption><thead><tr><th>Authors</th><th>Intervention</th><th>Blind</th><th>Evaluation of pain</th><th>Assessment in ON or OFF<sup>a</sup> state</th><th>TIDIER list completion</th><th>Adverse event (AE)</th><th>Results</th></tr></thead><tbody><tr><td colspan="8">Exercises</td></tr><tr><td colspan="8">Body-psychological practice</td></tr><tr><td>Pickut et al., 2015</td><td>Mind-Based Intervention<br>Usual care</td><td>Single-blind (assessor)</td><td>VAS</td><td>-</td><td>5/8</td><td>Acute back pain<br>-</td><td>A marginal significant interaction effect between groups (P = 0.07). No intragroup statistic realised</td></tr><tr><td colspan="8">Electromagnetic methods</td></tr><tr><td>Li et al., 2020</td><td>High-frequency repetitive<br>Transcranial Magnetic Stimulation (HF rTMS)<br>Sham HF rTMS</td><td>Double-blind (assessor & patients)</td><td>NRS (Primary Outcome)</td><td>ON</td><td>7/8</td><td>Headaches, dizziness, tinnitus, transient aggravation of gait disturbances (all acute)<br>Headaches, dizziness, tinnitus (all acute)</td><td>A significant difference between groups (P &lt; 0.001) was observed, with only the HF rTMS group exhibiting improvements in NRS scores at each follow-up time points (after the fifth intervention, 2-weeks and 4-weeks after) compared to baseline</td></tr><tr><td colspan="8">Multi-professional care</td></tr><tr><td>Gage et al., 2014</td><td>Specialist rehabilitation intervention:<br>Multidisciplinary Team care (MDT)</td><td>Single-blind (assessor)</td><td>VAS</td><td>ON and OFF</td><td>8/8</td><td>Falls, infections (chest, gastric, urinary), worsening symptoms and minor surgery (but not requiring hospital admission overnight)<br>There were sixty-nine serious adverse events (involving hospital stays or death) recorded for people with Parkinson's disease, and two for carers. These serious adverse events were judged expected by teams and there were no differences between groups</td><td>Some significant changes (degradation) in the MDT group between baseline and week 24 or 36, and in the control group between baseline and week 6, but globally no significant difference of pain evolution between groups (P &gt; 0.05)</td></tr><tr><td colspan="8">Ongoing support<br>Usual care</td></tr></tbody><tfoot><tr><td colspan="8"><sup>a</sup> OFF state is 12 h after medication withdrawal.<br><sup>b</sup> Gandolfi et al., 2019: T0 = before the treatment; T1 = two days after the end of the treatment; T2 = one-month follow-up after the end of the treatment;<br><sup>c</sup> Paolucci et al., 2017: T1 = at the end of the rehabilitative program; T2 = at 12-week follow-up.</td></tr></tfoot></table>
<table><caption>Table 3 (Continued)</caption><thead><tr><th>Authors</th><th>Intervention</th><th>Blind</th><th>Evaluation of pain</th><th>Assessment in ON or OFF<sup>a</sup> state</th><th>TIDIER list completion</th><th>Adverse event (AE)</th><th>Results</th></tr></thead><tbody><tr><td colspan="8">Exercises</td></tr><tr><td colspan="8">Body-psychological practice</td></tr><tr><td>Pickut et al., 2015</td><td>Mind-Based Intervention<br>Usual care</td><td>Single-blind<br>(assessor)</td><td>VAS</td><td>-</td><td>5/8</td><td>Acute back pain<br>-</td><td>A marginal significant interaction effect between groups (P = 0.07). No intragroup statistic realised</td></tr><tr><td colspan="8">Electromagnetic methods</td></tr><tr><td>Li et al., 2020</td><td>High-frequency repetitive<br>Transcranial Magnetic Stimulation<br>(HF rTMS)<br>Sham HF rTMS</td><td>Double-blind<br>(assessor & patients)</td><td>NRS (Primary Outcome)</td><td>ON</td><td>7/8</td><td>Headaches, dizziness, tinnitus, transient aggravation of gait disturbances (all acute)<br>Headaches, dizziness, tinnitus (all acute)</td><td>A significant difference between groups (P &lt; 0.001) was observed, with only the HF rTMS group exhibiting improvements in NRS scores at each follow-up time points (after the fifth intervention, 2-weeks and 4-weeks after) compared to baseline</td></tr><tr><td colspan="8">Multi-professional care</td></tr><tr><td>Gage et al., 2014</td><td>Specialist rehabilitation intervention:<br>Multidisciplinary Team care (MDT)</td><td>Single-blind<br>(assessor)</td><td>VAS</td><td>ON and OFF</td><td>8/8</td><td>Falls, infections (chest, gastric, urinary), worsening symptoms and minor surgery (but not requiring hospital admission overnight)<br>There were sixty-nine serious adverse events (involving hospital stays or death) recorded for people with Parkinson's disease, and two for carers. These serious adverse events were judged expected by teams and there were no differences between groups</td><td>Some significant changes (degradation) in the MDT group between baseline and week 24 or 36, and in the control group between baseline and week 6, but globally no significant difference of pain evolution between groups (P &gt; 0.05)</td></tr><tr><td colspan="8">Ongoing support<br>Usual care</td></tr></tbody><tfoot><tr><td colspan="8"><sup>a</sup> OFF state is 12 h after medication withdrawal.<br><sup>b</sup> Gandolfi et al., 2019: T0 = before the treatment; T1 = two days after the end of the treatment; T2 = one-month follow-up after the end of the treatment;<br><sup>c</sup> Paolucci et al., 2017: T1 = at the end of the rehabilitative program; T2 = at 12-week follow-up.</td></tr></tfoot></table>
a book [39]): exercise, balneotherapy, manual therapy, acupuncture, botanical preparation, body-psychological practice, and electromagnetic methods. Moreover, it was decided to add the multi-professional care category as an NPI. A qualitative analysis by type of intervention was then conducted to achieve the objectives of the review. The results were then discussed in terms of their scientific and medical relevance. Quantitative data is presented either with the mean ± standard error of the mean (SEM) or with the median, range and percentile according to studies available information.

### 3.6. Quality criteria: risk of bias (RoB)

To assess the risk of bias, the RoB2 tool for RCTs [40] was used. The same two authors (M.H. and M.B.) independently evaluated each study for the five domains of the RoB2 using the specified designed RoB2 tool either for parallel or crossover RCTs. Any conflict was resolved by discussion as recommended in the Cochrane handbook.

## 4. Results

### 4.1. Description of the flow chart

Search terms submitted to the databases led us to 711 records that two independent authors (M.H. and M.B.) investigated between January 2022 and March 2022. After deleting duplications, these records were firstly selected by their title in accordance to our eligibility criteria described in the method section. From the remaining 76 records, we excluded 57 after reading the abstracts. The selection was made following the PICO criteria and the majority of excluded articles were uncontrolled clinical trials (comparison) and/or without pain assessment (outcome). Then we added 32 titles that we considered relevant based on the references of the screened records, as well as seven articles identified from the supplementary research about neuromodulation. Finally, we read 58 full-text articles leading to the inclusion of 19 RCTs in our review.

### 4.2. Studies characteristics

The characteristics of the selected studies are presented in the Table 2. The studies were published between 2004 to 2021. Our review gathered data from 976 subjects, age range 50 to 79 years, and mean Hoehn and Yahr score between 1.5 and 3.0. The number of patients by study ranged from 15 to 270 subjects. All clinical trials were randomised and controlled with parallel groups except one that used a crossover design.

Study duration was from three weeks to one year including follow-up, which was the case for eleven studies (follow-up from four weeks to thirty weeks after the last intervention).

Two studies verified that all the patients had chronic pain either by including pain duration greater than three months as an inclusion criteria [41] or by only evaluating patients with musculoskeletal pain. This means that pain assessment in the

other studies was probably made both in patients with and without chronic pain.

To make sure PD patients were naive to the interventions, three studies noted whether the patient had experienced the intervention in a recent past (practice of Qigong in the last month [42] and history of receiving any kind of repetitive transcranial magnetic stimulation [rTMS] [43]) or at the present time (current yoga practice [44]) as an exclusion criteria.

Because description of the intervention is very important to be transferable into clinical practice, we assessed the reproducibility of these interventions using the TIDieR checklist [37]. Of the 19 RCTs, seven of them validated all items of the TIDieR checklist, ten missed one item and two missed more than one item.

### 4.3. Outcomes and pain assessment

Only three studies assessed pain as their primary outcome: one on Ai Chi aquatic physiotherapy [45], one on tactile touch [41] and one on high-frequency repetitive transcranial magnetic stimulation (HF rTMS) [43]. In the remaining studies, primary outcomes were mostly motor scores.

Three studies did not describe the time of the measurements while eleven assessed patients in the ON state, four in the OFF state and one in both ON and OFF states.

Twelve studies (63%) assessed pain with a unidimensional scale: a VAS in ten studies and a numeric rating scale (NRS) in two studies. For the others studies, a wide range of multidimensional pain assessments was used: either specialised pain questionnaires (McGill pain questionnaire [MPQ]) or non-specialised instruments such as the revised Oswestry disability index (RODI) or one item of the non-motor symptoms scale (NMSS). Finally, one study used both a qualitative (semi-structured interview) and a quantitative assessment (consumption of antalgic drugs [42]).

Except for two studies assessing musculoskeletal pain [43,46], the other RCTs did not mention the type of pain.

### 4.4. Non-pharmacological interventions (NPI)

Active therapy accounted for the majority of interventions (53%) performed by either a health specialist (physical therapist) or a non-health care specialist (Nordic walk or Qigong studies).

The following paragraphs present the global overview of the results, details are presented in Table 3.

#### 4.4.1. Physical exercises

In this category, seven different NPIs were found: each in a single investigation (there were no replication studies of these NPIs).

First, there were specific rehabilitation techniques, performed by qualified physical therapists: Lee Silverman voice treatment-BIG (LSVT-BIG); specific trunk rehabilitation; and the Meziere rehabilitation (Table 2 presents the characteristics of the interventions). None of these NPIs showed significant intergroup difference. However, in the LSVT-BIG study, the group that participated in the intensive physiotherapy – which was not the main intervention and consisted of an intensified

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a book [39]): exercise, balneotherapy, manual therapy, acupuncture, botanical preparation, body-psychological practice, and electromagnetic methods. Moreover, it was decided to add the multi-professional care category as an NPI. A qualitative analysis by type of intervention was then conducted to achieve the objectives of the review. The results were then discussed in terms of their scientific and medical relevance. Quantitative data is presented either with the mean ± standard error of the mean (SEM) or with the median, range and percentile according to studies available information.

### 3.6. Quality criteria: risk of bias (RoB)

To assess the risk of bias, the RoB2 tool for RCTs [40] was used. The same two authors (M.H. and M.B.) independently evaluated each study for the five domains of the RoB2 using the specified designed RoB2 tool either for parallel or crossover RCTs. Any conflict was resolved by discussion as recommended in the Cochrane handbook.

## 4. Results

### 4.1. Description of the flow chart

Search terms submitted to the databases led us to 711 records that two independent authors (M.H. and M.B.) investigated between January 2022 and March 2022. After deleting duplications, these records were firstly selected by their title in accordance to our eligibility criteria described in the method section. From the remaining 76 records, we excluded 57 after reading the abstracts. The selection was made following the PICO criteria and the majority of excluded articles were uncontrolled clinical trials (comparison) and/or without pain assessment (outcome). Then we added 32 titles that we considered relevant based on the references of the screened records, as well as seven articles identified from the supplementary research about neuromodulation. Finally, we read 58 full-text articles leading to the inclusion of 19 RCTs in our review.

### 4.2. Studies characteristics

The characteristics of the selected studies are presented in the Table 2. The studies were published between 2004 to 2021. Our review gathered data from 976 subjects, age range 50 to 79 years, and mean Hoehn and Yahr score between 1.5 and 3.0. The number of patients by study ranged from 15 to 270 subjects. All clinical trials were randomised and controlled with parallel groups except one that used a crossover design.

Study duration was from three weeks to one year including follow-up, which was the case for eleven studies (follow-up from four weeks to thirty weeks after the last intervention).

Two studies verified that all the patients had chronic pain either by including pain duration greater than three months as an inclusion criteria [41] or by only evaluating patients with musculoskeletal pain. This means that pain assessment in the

other studies was probably made both in patients with and without chronic pain.

To make sure PD patients were naive to the interventions, three studies noted whether the patient had experienced the intervention in a recent past (practice of Qigong in the last month [42] and history of receiving any kind of repetitive transcranial magnetic stimulation [rTMS] [43]) or at the present time (current yoga practice [44]) as an exclusion criteria.

Because description of the intervention is very important to be transferable into clinical practice, we assessed the reproducibility of these interventions using the TIDieR checklist [37]. Of the 19 RCTs, seven of them validated all items of the TIDieR checklist, ten missed one item and two missed more than one item.

### 4.3. Outcomes and pain assessment

Only three studies assessed pain as their primary outcome: one on Ai Chi aquatic physiotherapy [45], one on tactile touch [41] and one on high-frequency repetitive transcranial magnetic stimulation (HF rTMS) [43]. In the remaining studies, primary outcomes were mostly motor scores.

Three studies did not describe the time of the measurements while eleven assessed patients in the ON state, four in the OFF state and one in both ON and OFF states.

Twelve studies (63%) assessed pain with a unidimensional scale: a VAS in ten studies and a numeric rating scale (NRS) in two studies. For the others studies, a wide range of multidimensional pain assessments was used: either specialised pain questionnaires (McGill pain questionnaire [MPQ]) or non-specialised instruments such as the revised Oswestry disability index (RODI) or one item of the non-motor symptoms scale (NMSS). Finally, one study used both a qualitative (semi-structured interview) and a quantitative assessment (consumption of antalgic drugs [42]).

Except for two studies assessing musculoskeletal pain [43,46], the other RCTs did not mention the type of pain.

### 4.4. Non-pharmacological interventions (NPI)

Active therapy accounted for the majority of interventions (53%) performed by either a health specialist (physical therapist) or a non-health care specialist (Nordic walk or Qigong studies).

The following paragraphs present the global overview of the results, details are presented in Table 3.

#### 4.4.1. Physical exercises

In this category, seven different NPIs were found: each in a single investigation (there were no replication studies of these NPIs).

First, there were specific rehabilitation techniques, performed by qualified physical therapists: Lee Silverman voice treatment-BIG (LSVT-BIG); specific trunk rehabilitation; and the Meziere rehabilitation (Table 2 presents the characteristics of the interventions). None of these NPIs showed significant intergroup difference. However, in the LSVT-BIG study, the group that participated in the intensive physiotherapy – which was not the main intervention and consisted of an intensified

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and personalised physiotherapy – showed a significant improvement in the overall NMSS score compared to the control group. In the intragroup analyses, a decrease of pain was observed in both active and passive trunk rehabilitation groups as well as an improvement of pain in the Meziere rehabilitation group without improvement in the control group.

Regarding the other physical activities, for body weight supported treadmill training (BWSTT), intergroup comparison showed a significant decrease of pain for the two intervention groups (10% and 20% of body supports). In the same way, inside the groups, pain decreased only in both intervention groups while it increased in the control group (0% of body support).

Concerning Nordic walking, researchers found an improvement of pain in the back, hands and legs for both walking groups (Nordic walking and walking training) compared to the stretching and relaxation control group. Moreover, in the Nordic walking group up to 30% of the patients became free of pain after the training.

The Qigong intervention did not show any intergroup difference on pain compared to usual care, “although pain complaints tended to decrease only in the treatment group”. No intergroup comparison was presented for the yoga intervention, while intragroup analyses showed a decrease of pain only in the intervention group compared to the usual routine.

### 4.4.2. Balneotherapy

Three studies focused on the effect of balneotherapy versus dry physical therapy but only intragroup analyses were presented. Two studies found a significant decrease of pain in both groups, while the most recent study did not find significant difference in any groups.

### 4.4.3. Manual therapy

Two studies investigated manual therapy. Regarding the intergroup analysis, Thai massage seemed to provide a significant beneficial effect on pain in the intervention group in comparison with usual medical care. Conversely, therapeutic touch did not show significant long-term differences (34 weeks post-intervention) between the intervention and control groups, despite an emotional and physical improvement of pain at short-term (three weeks post-intervention) only in the intervention group through intragroup analyses.

### 4.4.4. Acupuncture

Electro-acupuncture (EA) was evaluated in two studies in comparison with placebo acupuncture, but intergroup analysis was not presented. In both studies, intragroup analyses did not find any significant improvement of pain in either group.

### 4.4.5. Botanical preparation

Two types of herbal preparations were evaluated in the literature: a cannabis-based preparation and a mixture called Jiawei Liujunzi Tang (JLT). Importantly, these two studies were the only ones to be conducted in a double-blind design. Both studies did not show any significant difference between the intervention and control groups on pain assessment. Intragroup analyses were not presented.

### 4.4.6. Body-psychological practice

A research studied the effect of a mind-based intervention (MBI) described as guided mindfulness exercises (meditation, yoga and body scan) to do at home. Intergroup analysis showed a tendency of beneficial effect on pain with the MBI. Intragroup analyses were not presented.

### 4.4.7. Electromagnetic methods

A research studied the effect of HF rTMS over the primary motor cortex in PD patients with musculoskeletal pain, compared to a sham intervention. Intergroup analysis showed a significant difference between groups: only the rTMS group had an improvement of pain after the intervention that persisted after follow-up.

### 4.4.8. Multi-professional care

A national study investigated the multidisciplinary follow-up of PD patients under a request from the English government. Patients were followed in hospital and at home with nursing, rehabilitation (physiotherapy, speech therapy), social support, and medical care. This study did not show any significant changes in pain between groups (intergroup analysis). However, they observed some significant changes (augmentation of pain) in the multidisciplinary team (MDT) group between baseline evaluation and evaluation at week 24 and 36, and in the control group from baseline to week 6 (intragroup analyses) in ON state. No significant difference in pain were found in OFF state.

### 4.5. Adverse events

In this wide range of interventions, reported adverse events were rare. Of the ten studies (52%) that mentioned adverse events, only one described serious adverse events involving hospital stays or death [47]. These serious adverse events were expected by the clinical research team regarding the number of participants and the study duration (250 PD patients followed for 36 weeks) and no difference was found between groups (intervention and control groups). The main minor adverse events were pain (muscle pain following exercise or abdominal pain), hypotension, transient headaches or dizziness, transient light-headedness and falls.

### 4.6. Quality of studies: risk of bias

To assess the risk of bias, the RoB2 tool of the Cochrane collaboration for RCT was used.

As can be seen in the Figs. 2 and 3, a large proportion of articles are considered to be at high risk of bias in the ‘outcome measurement’ domain (D4). In fact, in a large majority of studies (74%), the assessor (who was the patient for self-reported pain) was not blinded, which is considered as a high risk of bias.

## 5. Discussion

This review explores the benefits (effectiveness and safety) of NPIs for PD pain management, in a holistic approach. More precisely, studies were RCTs with pain assessment as a primary or secondary outcome.
and personalised physiotherapy – showed a significant improvement in the overall NMSS score compared to the control group. In the intragroup analyses, a decrease of pain was observed in both active and passive trunk rehabilitation groups as well as an improvement of pain in the Meziere rehabilitation group without improvement in the control group.

Regarding the other physical activities, for body weight supported treadmill training (BWSTT), intergroup comparison showed a significant decrease of pain for the two intervention groups (10% and 20% of body supports). In the same way, inside the groups, pain decreased only in both intervention groups while it increased in the control group (0% of body support).

Concerning Nordic walking, researchers found an improvement of pain in the back, hands and legs for both walking groups (Nordic walking and walking training) compared to the stretching and relaxation control group. Moreover, in the Nordic walking group up to 30% of the patients became free of pain after the training.

The Qigong intervention did not show any intergroup difference on pain compared to usual care, “although pain complaints tended to decrease only in the treatment group”. No intergroup comparison was presented for the yoga intervention, while intragroup analyses showed a decrease of pain only in the intervention group compared to the usual routine.

### 4.4.2. Balneotherapy

Three studies focused on the effect of balneotherapy versus dry physical therapy but only intragroup analyses were presented. Two studies found a significant decrease of pain in both groups, while the most recent study did not find significant difference in any groups.

### 4.4.3. Manual therapy

Two studies investigated manual therapy. Regarding the intergroup analysis, Thai massage seemed to provide a significant beneficial effect on pain in the intervention group in comparison with usual medical care. Conversely, therapeutic touch did not show significant long-term differences (34 weeks post-intervention) between the intervention and control groups, despite an emotional and physical improvement of pain at short-term (three weeks post-intervention) only in the intervention group through intragroup analyses.

### 4.4.4. Acupuncture

Electro-acupuncture (EA) was evaluated in two studies in comparison with placebo acupuncture, but intergroup analysis was not presented. In both studies, intragroup analyses did not find any significant improvement of pain in either group.

### 4.4.5. Botanical preparation

Two types of herbal preparations were evaluated in the literature: a cannabis-based preparation and a mixture called Jiawei Liujunzi Tang (JLT). Importantly, these two studies were the only ones to be conducted in a double-blind design. Both studies did not show any significant difference between the intervention and control groups on pain assessment. Intragroup analyses were not presented.

### 4.4.6. Body-psychological practice

A research studied the effect of a mind-based intervention (MBI) described as guided mindfulness exercises (meditation, yoga and body scan) to do at home. Intergroup analysis showed a tendency of beneficial effect on pain with the MBI. Intragroup analyses were not presented.

### 4.4.7. Electromagnetic methods

A research studied the effect of HF rTMS over the primary motor cortex in PD patients with musculoskeletal pain, compared to a sham intervention. Intergroup analysis showed a significant difference between groups: only the rTMS group had an improvement of pain after the intervention that persisted after follow-up.

### 4.4.8. Multi-professional care

A national study investigated the multidisciplinary follow-up of PD patients under a request from the English government. Patients were followed in hospital and at home with nursing, rehabilitation (physiotherapy, speech therapy), social support, and medical care. This study did not show any significant changes in pain between groups (intergroup analysis). However, they observed some significant changes (augmentation of pain) in the multidisciplinary team (MDT) group between baseline evaluation and evaluation at week 24 and 36, and in the control group from baseline to week 6 (intragroup analyses) in ON state. No significant difference in pain were found in OFF state.

### 4.5. Adverse events

In this wide range of interventions, reported adverse events were rare. Of the ten studies (52%) that mentioned adverse events, only one described serious adverse events involving hospital stays or death [47]. These serious adverse events were expected by the clinical research team regarding the number of participants and the study duration (250 PD patients followed for 36 weeks) and no difference was found between groups (intervention and control groups). The main minor adverse events were pain (muscle pain following exercise or abdominal pain), hypotension, transient headaches or dizziness, transient light-headedness and falls.

### 4.6. Quality of studies: risk of bias

To assess the risk of bias, the RoB2 tool of the Cochrane collaboration for RCT was used.

As can be seen in the Figs. 2 and 3, a large proportion of articles are considered to be at high risk of bias in the ‘outcome measurement’ domain (D4). In fact, in a large majority of studies (74%), the assessor (who was the patient for self-reported pain) was not blinded, which is considered as a high risk of bias.

## 5. Discussion

This review explores the benefits (effectiveness and safety) of NPIs for PD pain management, in a holistic approach. More precisely, studies were RCTs with pain assessment as a primary or secondary outcome.
<figure><img src="image_3.png" /><figcaption>Fig. 2 – Risk of bias as percentage (all studies included).</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>Fig. 3 – Risk of bias for each study. D: domain.</figcaption></figure>

## 5.1. Effectiveness of non-pharmacological interventions

Results have shown that NPIs had a low-to-moderate level of evidence for PD pain management, with favourable or inconclusive results. This could be due to the small sample size of the studies or to the choice of assessment methods, which were probably not specific or sensitive enough to assess changes in PD pain. These results must be considered with great caution because of the arguments outlined below.

In our review, the effects of NPIs can be summarized into four categories:

* NPIs (n = 5) that have shown a significant effect on PD pain compared to their control group (intergroup analyses). This is the case for Thai massage, Nordic walking, BWSTT, MBI and HF rTMS;

* NPIs (n = 5) that did not show intergroup differences (absence of statistical analyses or non-significant results)

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<figure><img src="image_3.png" /><figcaption>Fig. 2 – Risk of bias as percentage (all studies included).</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>Fig. 3 – Risk of bias for each study. D: domain.</figcaption></figure>

## 5.1. Effectiveness of non-pharmacological interventions

Results have shown that NPIs had a low-to-moderate level of evidence for PD pain management, with favourable or inconclusive results. This could be due to the small sample size of the studies or to the choice of assessment methods, which were probably not specific or sensitive enough to assess changes in PD pain. These results must be considered with great caution because of the arguments outlined below.

In our review, the effects of NPIs can be summarized into four categories:

* NPIs (n = 5) that have shown a significant effect on PD pain compared to their control group (intergroup analyses). This is the case for Thai massage, Nordic walking, BWSTT, MBI and HF rTMS;

* NPIs (n = 5) that did not show intergroup differences (absence of statistical analyses or non-significant results)

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but where an improvement of pain was only observed within the intervention group (and not in the control group). This is the case for tactile touch, Qigong, yoga, the Meziere rehabilitation and trunk-specific rehabilitation;

* NPIs (n = 4) whose results did not allow to conclude on their effect on PD pain management: both the intervention and control groups showed significant changes in the same direction but without significant intergroup comparison. This is the case for aquatic Ai Chi (n = 2) (both the control and intervention groups showed improvements of pain), electro-acupuncture, and for the multidisciplinary management (aggravation of pain was observed in both groups);

* NPIs (n = 5) that did not show any significant differences either in inter- or intra-groups comparisons. This is the case for intensive physiotherapy in water, LSVT-BIG technique, electro-acupuncture, JLT and cannabis.

Regarding these previous categories, it seems that NPIs where the patient was active (exercises and body-psychological practice from the NPIs classification [39]: three studies out of five that showed a significant effect on PD pain compared to their control group) had a more significant impact to decrease PD pain than NPIs where the patient was passive. These benefits could be explained by the effect of physical activity on neuroplasticity, neuro-restoration and improvement of dopamine neurotransmission, as shown on animal models of PD [48]. These findings support the hypothesis that the benefits of NPIs emerge through a process of patient empowerment, active problem solving, realistic goal setting, and a functional/rehabilitative perspective [31].

According to our results, NPIs resulting from passive interventions, such as vitamins, herbs, cannabis, or acupuncture, seem to be less effective on pain, except for Thai massage and HF rTMS.

## 5.2. Evaluation of pain

Pain is a complex construct to assess because it is a multimodal sensation, with biopsychosocial dimensions: sensory-discriminative, affective-emotional, cognitive and behavioural. Pain questionnaires are rarely validated for PD pain, despite a recommended list of specific questionnaires to assess PD pain [49]. Through the seven questionnaires recommended with caution, only four were used in this review (MPQ, NRS, VAS, pain-o-meter). However, even when they are, their results are often not comparable because they do not assess the same type and dimension of pain.

Furthermore, we can point out that there were only three studies in which pain was the primary outcome and all assessed pain with a unidimensional scale (either by the VAS, which was the most commonly used scale in our review's studies, or the NRS). In four studies, the assessment of pain intensity was only done in the OFF-medication state, which can be considered irrelevant as it does not represent the patients' daily life.

Finally, there are different types of PD pain [5] corresponding to different mechanisms that should be treated with specific therapy. Indeed, pain treatment should probably not be etiology-driven, but rather mechanism-based [6]: this is why the characterisation of the different subgroups of PD pain

is so important [5]. Nevertheless, only two of the studies in our review defined which type of pain was assessed. In future studies, it could be interesting to specify the types of pain with the aim of adapting the management strategy as well as possible. For example, it is conceivable that NPIs modulating neuroplasticity might have a better effect on nociceptive pain.

## 5.3. Quality of non-pharmacological interventions studies

These results should be viewed with great caution due to the methodological limitations of the studies. These limitations may relate to the lack of blinding, the control group and/or the duration of the study.

Firstly, for the three studies with pain as the primary endpoint, only one was double-blind, while one was single-blind and the other was open-label. Including the other studies, only six (31%) were double-blind. Therefore, a majority of studies are rated as high risk of bias by the RoB2 tool.

The second methodological limitation is the lack of a suitable control group. It could be explained by the inherent characteristics of NPIs. Indeed, it is difficult to construct a control group that mimics the active intervention without containing its active ingredients, so the control group often constitutes another form of NPI that improves the patient's condition and reduces the magnitude of the specific effect of the NPI.

The control group may be (i) a control group (without any standard intervention or treatment); (ii) a sham intervention group (intervention with the same time and type of interaction with the patient but without a supposed specific effect); or (iii) another intervention modality (e.g., medication, therapeutic education, physical activity program). Concerning the three studies with pain as a primary objective, control groups were adequate since they properly isolated the specific NPI induced-effect and patients in both groups had the same number of sessions and duration of study. Nonetheless, we cannot exclude that these control groups constitute another form of NPI. Concerning the remaining studies, some had discrepancies between their control and intervention groups about the planning; while others used control groups too different from the intervention group to truly isolate NPI specific effect.

Thirdly, duration of the study could also be an important feature to consider when reviewing the quality of the studies.

In the three studies where pain was the primary endpoint, the interventions were conducted during five to twenty sessions. Except for the rTMS sessions which were all performed during the same week, both other interventions were carried out between seven and ten weeks, which seems to be a good length of time to study the effect of NPIs. Indeed, the literature advises a study duration of ideally twelve weeks, with a minimum of eight weeks, for chronic pain [50]. The remaining studies tended to be sufficiently long because of the median duration of twelve weeks.

Nevertheless, three studies (16%) had a duration of four weeks or less (follow-up included), which may overestimate effectiveness [50].

Finally, concerning the three studies with pain as the primary outcome [41,45], one of them [45] can be criticised

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but where an improvement of pain was only observed within the intervention group (and not in the control group). This is the case for tactile touch, Qigong, yoga, the Meziere rehabilitation and trunk-specific rehabilitation;

* NPIs (n = 4) whose results did not allow to conclude on their effect on PD pain management: both the intervention and control groups showed significant changes in the same direction but without significant intergroup comparison. This is the case for aquatic Ai Chi (n = 2) (both the control and intervention groups showed improvements of pain), electro-acupuncture, and for the multidisciplinary management (aggravation of pain was observed in both groups);

* NPIs (n = 5) that did not show any significant differences either in inter- or intra-groups comparisons. This is the case for intensive physiotherapy in water, LSVT-BIG technique, electro-acupuncture, JLT and cannabis.

Regarding these previous categories, it seems that NPIs where the patient was active (exercises and body-psychological practice from the NPIs classification [39]: three studies out of five that showed a significant effect on PD pain compared to their control group) had a more significant impact to decrease PD pain than NPIs where the patient was passive. These benefits could be explained by the effect of physical activity on neuroplasticity, neuro-restoration and improvement of dopamine neurotransmission, as shown on animal models of PD [48]. These findings support the hypothesis that the benefits of NPIs emerge through a process of patient empowerment, active problem solving, realistic goal setting, and a functional/rehabilitative perspective [31].

According to our results, NPIs resulting from passive interventions, such as vitamins, herbs, cannabis, or acupuncture, seem to be less effective on pain, except for Thai massage and HF rTMS.

## 5.2. Evaluation of pain

Pain is a complex construct to assess because it is a multimodal sensation, with biopsychosocial dimensions: sensory-discriminative, affective-emotional, cognitive and behavioural. Pain questionnaires are rarely validated for PD pain, despite a recommended list of specific questionnaires to assess PD pain [49]. Through the seven questionnaires recommended with caution, only four were used in this review (MPQ, NRS, VAS, pain-o-meter). However, even when they are, their results are often not comparable because they do not assess the same type and dimension of pain.

Furthermore, we can point out that there were only three studies in which pain was the primary outcome and all assessed pain with a unidimensional scale (either by the VAS, which was the most commonly used scale in our review's studies, or the NRS). In four studies, the assessment of pain intensity was only done in the OFF-medication state, which can be considered irrelevant as it does not represent the patients' daily life.

Finally, there are different types of PD pain [5] corresponding to different mechanisms that should be treated with specific therapy. Indeed, pain treatment should probably not be etiology-driven, but rather mechanism-based [6]: this is why the characterisation of the different subgroups of PD pain

is so important [5]. Nevertheless, only two of the studies in our review defined which type of pain was assessed. In future studies, it could be interesting to specify the types of pain with the aim of adapting the management strategy as well as possible. For example, it is conceivable that NPIs modulating neuroplasticity might have a better effect on nociceptive pain.

## 5.3. Quality of non-pharmacological interventions studies

These results should be viewed with great caution due to the methodological limitations of the studies. These limitations may relate to the lack of blinding, the control group and/or the duration of the study.

Firstly, for the three studies with pain as the primary endpoint, only one was double-blind, while one was single-blind and the other was open-label. Including the other studies, only six (31%) were double-blind. Therefore, a majority of studies are rated as high risk of bias by the RoB2 tool.

The second methodological limitation is the lack of a suitable control group. It could be explained by the inherent characteristics of NPIs. Indeed, it is difficult to construct a control group that mimics the active intervention without containing its active ingredients, so the control group often constitutes another form of NPI that improves the patient's condition and reduces the magnitude of the specific effect of the NPI.

The control group may be (i) a control group (without any standard intervention or treatment); (ii) a sham intervention group (intervention with the same time and type of interaction with the patient but without a supposed specific effect); or (iii) another intervention modality (e.g., medication, therapeutic education, physical activity program). Concerning the three studies with pain as a primary objective, control groups were adequate since they properly isolated the specific NPI induced-effect and patients in both groups had the same number of sessions and duration of study. Nonetheless, we cannot exclude that these control groups constitute another form of NPI. Concerning the remaining studies, some had discrepancies between their control and intervention groups about the planning; while others used control groups too different from the intervention group to truly isolate NPI specific effect.

Thirdly, duration of the study could also be an important feature to consider when reviewing the quality of the studies.

In the three studies where pain was the primary endpoint, the interventions were conducted during five to twenty sessions. Except for the rTMS sessions which were all performed during the same week, both other interventions were carried out between seven and ten weeks, which seems to be a good length of time to study the effect of NPIs. Indeed, the literature advises a study duration of ideally twelve weeks, with a minimum of eight weeks, for chronic pain [50]. The remaining studies tended to be sufficiently long because of the median duration of twelve weeks.

Nevertheless, three studies (16%) had a duration of four weeks or less (follow-up included), which may overestimate effectiveness [50].

Finally, concerning the three studies with pain as the primary outcome [41,45], one of them [45] can be criticised
because it was almost identical to another study in our review done by the same author [51]. This makes us question its veracity since there are some inconsistencies between the demographic data presented in the text and in the table in the second one [51].

In the same way, both studies about electro-acupuncture [52,53] present identical demographic data and results, which seems improbable.

## 5.4. Safety of non-pharmacological interventions

Some studies reported few minor transient adverse events. Only one study documented some serious adverse events probably explained by evolution of the disease through the study. Given this information, it would appear reasonable to consider NPIs as safe in PD pain management.

## 5.5. Limits and strengths

The limitations of our review result from a lack of information in the study reports, although this can easily be justified as pain was often not the primary assessment in the studies. Another limit is the absence of PD pain classification, as mentioned before, forcing us to treat all results on equal terms, while nociceptive, neuropathic or nociplastic pain could respond differently to various NPIs. NPIs effects cannot be generalised but need to be deconstructed and their specificities associated with the mechanisms underlying the therapeutic effect correlated to each type of pain.

The strength of our review is that it was made very carefully following the PRISMA recommendations and that reproducibility of NPIs were well evaluated using the TIDieR checklist.

# 6. Conclusion and implication for future research

Our review highlighted the clinical relevance of some NPIs in PD pain management, in particular NPIs where the patient was active (exercises and body-psychological practice), and the safety of NPIs since only a few minor transient adverse effects were reported. Hence, according to our results categorisation, we could recommend Thai massage, Nordic walking, BSWTT, MBI and HF rTMS as effective NPIs to relieve PD pain.

Nevertheless, even if we have found some interesting results, differentiating NPIs superiority was difficult because of the absence of standardised measurement procedures, the variety of outcomes, and the limited number of high-quality studies. The methodology of future studies also needs to be more robust and to include comprehensive descriptions in order to be replicated and to offer reliable and sound recommendations to clinicians.

Specifically, pain evaluation needs to be assessed with robust tools and validated PD pain classifications in order to be precise about the type of pain studied. In addition, the promising scientific evidence supporting the concept of biopsychosocially mediated analgesia must be translated into an assessment of the biopsychosocial dimensions of pain. This

new perspective on pain management should allow us to study NPIs in a new framework and to understand the mechanisms underlying their effect, to dissect their active effects and to look at the patients' profiles (responders, non-responders, personality dimensions...). This will allow clinicians to propose NPIs according to PD pain types and patient profiles, in a personalised medicine concept.

To this end, we would like to encourage future studies to be conducted in this area by addressing the following criteria to improve the reports:

* explanation of the relevance of the evaluation criteria (feasibility of their gathering, traceability, availability of information, clarity and absence of ambiguity of the criteria, margin of improvement, expected impact on the results, compliance of patients);

* adequate control group with a justification;

* evaluation performed on biopsychosocial dimensions of pain;

* adequate duration of follow-up.

## Disclosure of interest

The authors declare that they have no competing interest.

## Funding

There has been no significant financial support for this work that could have influenced its outcome.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.neurol.2023.04.010.

## REFERENCES

[1] Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson's disease. Neuropsychiatr Dis Treat 2008;4(4):743-57.

[2] Chaudhuri KR, Schapira AHV. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8(5):464-74. http://dx.doi.org/10.1016/S1474-4422(09)70068-7.

[3] Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson's disease in primary care: a case-control study. Lancet Neurol 2015;14(1):57-64. http://dx.doi.org/10.1016/S1474-4422(14)70287-X.

[4] Negre-Pages L, Regragui W, Bouhassira D, Grandjean H, Rascol O. Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP Survey. Chronic Pain Park Dis Cross-Sect Fr DoPaMiP Surv 2008;23(10):1361-9.

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because it was almost identical to another study in our review done by the same author [51]. This makes us question its veracity since there are some inconsistencies between the demographic data presented in the text and in the table in the second one [51].

In the same way, both studies about electro-acupuncture [52,53] present identical demographic data and results, which seems improbable.

## 5.4. Safety of non-pharmacological interventions

Some studies reported few minor transient adverse events. Only one study documented some serious adverse events probably explained by evolution of the disease through the study. Given this information, it would appear reasonable to consider NPIs as safe in PD pain management.

## 5.5. Limits and strengths

The limitations of our review result from a lack of information in the study reports, although this can easily be justified as pain was often not the primary assessment in the studies. Another limit is the absence of PD pain classification, as mentioned before, forcing us to treat all results on equal terms, while nociceptive, neuropathic or nociplastic pain could respond differently to various NPIs. NPIs effects cannot be generalised but need to be deconstructed and their specificities associated with the mechanisms underlying the therapeutic effect correlated to each type of pain.

The strength of our review is that it was made very carefully following the PRISMA recommendations and that reproducibility of NPIs were well evaluated using the TIDieR checklist.

# 6. Conclusion and implication for future research

Our review highlighted the clinical relevance of some NPIs in PD pain management, in particular NPIs where the patient was active (exercises and body-psychological practice), and the safety of NPIs since only a few minor transient adverse effects were reported. Hence, according to our results categorisation, we could recommend Thai massage, Nordic walking, BSWTT, MBI and HF rTMS as effective NPIs to relieve PD pain.

Nevertheless, even if we have found some interesting results, differentiating NPIs superiority was difficult because of the absence of standardised measurement procedures, the variety of outcomes, and the limited number of high-quality studies. The methodology of future studies also needs to be more robust and to include comprehensive descriptions in order to be replicated and to offer reliable and sound recommendations to clinicians.

Specifically, pain evaluation needs to be assessed with robust tools and validated PD pain classifications in order to be precise about the type of pain studied. In addition, the promising scientific evidence supporting the concept of biopsychosocially mediated analgesia must be translated into an assessment of the biopsychosocial dimensions of pain. This

new perspective on pain management should allow us to study NPIs in a new framework and to understand the mechanisms underlying their effect, to dissect their active effects and to look at the patients' profiles (responders, non-responders, personality dimensions...). This will allow clinicians to propose NPIs according to PD pain types and patient profiles, in a personalised medicine concept.

To this end, we would like to encourage future studies to be conducted in this area by addressing the following criteria to improve the reports:

* explanation of the relevance of the evaluation criteria (feasibility of their gathering, traceability, availability of information, clarity and absence of ambiguity of the criteria, margin of improvement, expected impact on the results, compliance of patients);

* adequate control group with a justification;

* evaluation performed on biopsychosocial dimensions of pain;

* adequate duration of follow-up.

## Disclosure of interest

The authors declare that they have no competing interest.

## Funding

There has been no significant financial support for this work that could have influenced its outcome.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.neurol.2023.04.010.

## REFERENCES

[1] Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson's disease. Neuropsychiatr Dis Treat 2008;4(4):743-57.

[2] Chaudhuri KR, Schapira AHV. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8(5):464-74. http://dx.doi.org/10.1016/S1474-4422(09)70068-7.

[3] Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson's disease in primary care: a case-control study. Lancet Neurol 2015;14(1):57-64. http://dx.doi.org/10.1016/S1474-4422(14)70287-X.

[4] Negre-Pages L, Regragui W, Bouhassira D, Grandjean H, Rascol O. Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP Survey. Chronic Pain Park Dis Cross-Sect Fr DoPaMiP Surv 2008;23(10):1361-9.

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[5] Marques A, Attal N, Bouhassira D, Moisset X, Cantagrel N, Rascol O, et al. How to diagnose Parkinsonian central pain? Parkinsonism Relat Disord 2019;64:50-3.

[6] Mylius V, Perez Lloret S, Cury RG, Teixeira MJ, Barbosa VR, Barbosa ER, et al. The Parkinson disease pain classification system: results from an international mechanism-based classification approach. Pain 2021;162(4):1201-10.

[7] Tseng MT, Lin CH. Pain in early-stage Parkinson's disease: implications from clinical features to pathophysiology mechanisms. J Formos Med Assoc Taiwan Yi Zhi 2017;116(8):571-81. http://dx.doi.org/10.1016/j.jfma.2017.04.024.

[8] Berardelli A, Conte A, Fabbrini G, Bologna M, Latorre A, Rocchi L, et al. Pathophysiology of pain and fatigue in Parkinson's disease. Parkinsonism Relat Disord 2012;18(Suppl. 1):S226-8.

[9] Fil A, Cano-de-la-Cuerda R, Muñoz-Hellín E, Vela L, Ramiro-González M, Fernández-de-las-Peñas C. Pain in Parkinson disease: a review of the literature. Parkinsonism Relat Disord 2013;19(3):285-94. http://dx.doi.org/10.1016/j.parkreldis.2012.11.009.

[10] Sung S, Vijiaratnam N, Chan DWC, Farrell M, Evans AH. Parkinson disease: a systemic review of pain sensitivities and its association with clinical pain and response to dopaminergic stimulation. J Neurol Sci 2018;395:172-206. http://dx.doi.org/10.1016/j.jns.2018.10.013.

[11] Li J, Zhu BF, Gu ZQ, Zhang H, Mei SS, Ji SZ, et al. Musculoskeletal pain in Parkinson's disease. Front Neurol [Internet] 2022;12 [cited 20 mars 2023. Disponible sur : https://www.frontiersin.org/articles/10.3389/fneur.2021.756538].

[12] Thompson T, Gallop K, Correll CU, Carvalho AF, Veronese N, Wright E, et al. Pain perception in Parkinson's disease: a systematic review and meta-analysis of experimental studies. Ageing Res Rev 2017;35:74-86.

[13] Brefel-Courbon C, Ory-Magne F, Thalamas C, Payoux P, Rascol O. Nociceptive brain activation in patients with neuropathic pain related to Parkinson's disease. Parkinsonism Relat Disord 2013;19(5):548-52. http://dx.doi.org/10.1016/j.parkreldis.2013.02.003.

[14] Marques A, Brefel-Courbon C. Chronic pain in Parkinson's disease: clinical and pathophysiological aspects. Rev Neurol (Paris) 2021;177(4):394-9. http://dx.doi.org/10.1016/j.neurol.2020.06.015.

[15] Karnik V, Farcy N, Zamorano C, Bruno V. Current status of pain management in Parkinson's disease. Can J Neurol Sci J Can Sci Neurol 2020;47(3):336-43. http://dx.doi.org/10.1017/cjn.2020.13.

[16] Lawn T, Aman Y, Rukavina K, Sideris-Lampretsas G, Howard M, Ballard C, et al. Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease. Pain 2021;162(4):999-1006.

[17] Trenkwalder C, Chaudhuri KR, Martinez-Martin P, Rascol O, Ehret R, Vališ M, et al. Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol 2015;14(12):1161-70.

[18] Qureshi AR, Rana AQ, Malik SH, Rizvi SFH, Akhter S, Vannabouathong C, et al. Comprehensive examination of therapies for pain in Parkinson's disease: a systematic review and meta-analysis. Neuroepidemiology 2018;51(3-4):190-206.

[19] Dellapina E, Ory-Magne F, Regragui W, Thalamas C, Lazorthes Y, Rascol O, et al. Effect of subthalamic deep brain stimulation on pain in Parkinson's disease. Pain 2012;153(11):2267-73.

[20] Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, et al. Expert Consensus

Group report on the use of apomorphine in the treatment of Parkinson's disease - Clinical practice recommendations. Parkinsonism Relat Disord 2015;21(9):1023-30.

[21] Rascol O, Zesiewicz T, Chaudhuri KR, Asgharnejad M, Surmann E, Dohin E, et al. A randomized controlled exploratory pilot study to evaluate the effect of rotigotine transdermal patch on Parkinson's disease-associated chronic pain. J Clin Pharmacol 2016;56(7):852-61.

[22] Cury RG, Galhardoni R, Fonoff ET, Dos Santos Ghilardi MG, Fonoff F, Arnaut D, et al. Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease. Neurology 2014;83(16):1403-9.

[23] Marques A, Chassin O, Morand D, Pereira B, Debilly B, Derost P, et al. Central pain modulation after subthalamic nucleus stimulation: a crossover randomized trial. Neurology 2013;81(7):633-40.

[24] Pellaprat J, Ory-Magne F, Canivet C, Simonetta-Moreau M, Lotterie JA, Radji F, et al. Deep brain stimulation of the subthalamic nucleus improves pain in Parkinson's disease. Parkinsonism Relat Disord 2014;20(6):662-4.

[25] Tick H, Nielsen A, Pelletier KR, Bonakdar R, Simmons S, Glick R, et al. Evidence-based nonpharmacologic strategies for comprehensive pain care: the Consortium Pain Task Force White Paper. Explore (NY) 2018;14(3):177-211.

[26] Gandolfi M, Geroin C, Antonini A, Smania N, Tinazzi M. Understanding and treating pain syndromes in Parkinson's disease. Int Rev Neurobiol 2017;134:827-58. http://dx.doi.org/10.1016/bs.im.2017.05.013.

[27] Sung S, Farrell M, Vijiaratnam N, Evans AH. Pain and dyskinesia in Parkinson's disease may share common pathophysiological mechanisms - An fMRI study. J Neurol Sci 2020;416:116905. http://dx.doi.org/10.1016/j.jns.2020.116905.

[28] Rabinstein AA, Shulman LM. Acupuncture in clinical neurology. The Neurologist 2003;9(3):137-48. http://dx.doi.org/10.1097/00127893-200305000-00002.

[29] Rajendran PR, Thompson RE, Reich SG. The use of alternative therapies by patients with Parkinson's disease. Neurology 2001;57(5):790-4. http://dx.doi.org/10.1212/wnl.57.5.790.

[30] Kundakci B, Kaur J, Goh SL, Hall M, Doherty M, Zhang W, et al. Efficacy of nonpharmacological interventions for individual features of fibromyalgia: a systematic review and meta-analysis of randomised controlled trials. Pain 2022;163(8):1432-45.

[31] Becker WC, Dorflinger L, Edmond SN, Islam L, Heapy AA, Fraenkel L. Barriers and facilitators to use of non-pharmacological treatments in chronic pain. BMC Fam Pract 2017;18(1):41. http://dx.doi.org/10.1186/s12875-017-0608-2.

[32] Wamelen DJV, Rukavina K, Podlewska AM, Chaudhuri KR. Advances in the pharmacological and non-pharmacological management of non-motor symptoms in Parkinson's disease: an update since 2017. Curr Neuropharmacol 2022. http://dx.doi.org/10.2174/1570159X20666220315163856 [Published online March 15].

[33] Deuel LM, Seeberger LC. Complementary therapies in Parkinson disease: a review of acupuncture, tai chi, Qi Gong, yoga, and cannabis. Neurother J Am Soc Exp Neurother 2020;17(4):1434-55. http://dx.doi.org/10.1007/s13311-020-00900-y.

[34] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.

[35] Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019.

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[5] Marques A, Attal N, Bouhassira D, Moisset X, Cantagrel N, Rascol O, et al. How to diagnose Parkinsonian central pain? Parkinsonism Relat Disord 2019;64:50-3.

[6] Mylius V, Perez Lloret S, Cury RG, Teixeira MJ, Barbosa VR, Barbosa ER, et al. The Parkinson disease pain classification system: results from an international mechanism-based classification approach. Pain 2021;162(4):1201-10.

[7] Tseng MT, Lin CH. Pain in early-stage Parkinson's disease: implications from clinical features to pathophysiology mechanisms. J Formos Med Assoc Taiwan Yi Zhi 2017;116(8):571-81. http://dx.doi.org/10.1016/j.jfma.2017.04.024.

[8] Berardelli A, Conte A, Fabbrini G, Bologna M, Latorre A, Rocchi L, et al. Pathophysiology of pain and fatigue in Parkinson's disease. Parkinsonism Relat Disord 2012;18(Suppl. 1):S226-8.

[9] Fil A, Cano-de-la-Cuerda R, Muñoz-Hellín E, Vela L, Ramiro-González M, Fernández-de-las-Peñas C. Pain in Parkinson disease: a review of the literature. Parkinsonism Relat Disord 2013;19(3):285-94. http://dx.doi.org/10.1016/j.parkreldis.2012.11.009.

[10] Sung S, Vijiaratnam N, Chan DWC, Farrell M, Evans AH. Parkinson disease: a systemic review of pain sensitivities and its association with clinical pain and response to dopaminergic stimulation. J Neurol Sci 2018;395:172-206. http://dx.doi.org/10.1016/j.jns.2018.10.013.

[11] Li J, Zhu BF, Gu ZQ, Zhang H, Mei SS, Ji SZ, et al. Musculoskeletal pain in Parkinson's disease. Front Neurol [Internet] 2022;12 [cited 20 mars 2023. Disponible sur : https://www.frontiersin.org/articles/10.3389/fneur.2021.756538].

[12] Thompson T, Gallop K, Correll CU, Carvalho AF, Veronese N, Wright E, et al. Pain perception in Parkinson's disease: a systematic review and meta-analysis of experimental studies. Ageing Res Rev 2017;35:74-86.

[13] Brefel-Courbon C, Ory-Magne F, Thalamas C, Payoux P, Rascol O. Nociceptive brain activation in patients with neuropathic pain related to Parkinson's disease. Parkinsonism Relat Disord 2013;19(5):548-52. http://dx.doi.org/10.1016/j.parkreldis.2013.02.003.

[14] Marques A, Brefel-Courbon C. Chronic pain in Parkinson's disease: clinical and pathophysiological aspects. Rev Neurol (Paris) 2021;177(4):394-9. http://dx.doi.org/10.1016/j.neurol.2020.06.015.

[15] Karnik V, Farcy N, Zamorano C, Bruno V. Current status of pain management in Parkinson's disease. Can J Neurol Sci J Can Sci Neurol 2020;47(3):336-43. http://dx.doi.org/10.1017/cjn.2020.13.

[16] Lawn T, Aman Y, Rukavina K, Sideris-Lampretsas G, Howard M, Ballard C, et al. Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease. Pain 2021;162(4):999-1006.

[17] Trenkwalder C, Chaudhuri KR, Martinez-Martin P, Rascol O, Ehret R, Vališ M, et al. Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol 2015;14(12):1161-70.

[18] Qureshi AR, Rana AQ, Malik SH, Rizvi SFH, Akhter S, Vannabouathong C, et al. Comprehensive examination of therapies for pain in Parkinson's disease: a systematic review and meta-analysis. Neuroepidemiology 2018;51(3-4):190-206.

[19] Dellapina E, Ory-Magne F, Regragui W, Thalamas C, Lazorthes Y, Rascol O, et al. Effect of subthalamic deep brain stimulation on pain in Parkinson's disease. Pain 2012;153(11):2267-73.

[20] Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, et al. Expert Consensus

Group report on the use of apomorphine in the treatment of Parkinson's disease - Clinical practice recommendations. Parkinsonism Relat Disord 2015;21(9):1023-30.

[21] Rascol O, Zesiewicz T, Chaudhuri KR, Asgharnejad M, Surmann E, Dohin E, et al. A randomized controlled exploratory pilot study to evaluate the effect of rotigotine transdermal patch on Parkinson's disease-associated chronic pain. J Clin Pharmacol 2016;56(7):852-61.

[22] Cury RG, Galhardoni R, Fonoff ET, Dos Santos Ghilardi MG, Fonoff F, Arnaut D, et al. Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease. Neurology 2014;83(16):1403-9.

[23] Marques A, Chassin O, Morand D, Pereira B, Debilly B, Derost P, et al. Central pain modulation after subthalamic nucleus stimulation: a crossover randomized trial. Neurology 2013;81(7):633-40.

[24] Pellaprat J, Ory-Magne F, Canivet C, Simonetta-Moreau M, Lotterie JA, Radji F, et al. Deep brain stimulation of the subthalamic nucleus improves pain in Parkinson's disease. Parkinsonism Relat Disord 2014;20(6):662-4.

[25] Tick H, Nielsen A, Pelletier KR, Bonakdar R, Simmons S, Glick R, et al. Evidence-based nonpharmacologic strategies for comprehensive pain care: the Consortium Pain Task Force White Paper. Explore (NY) 2018;14(3):177-211.

[26] Gandolfi M, Geroin C, Antonini A, Smania N, Tinazzi M. Understanding and treating pain syndromes in Parkinson's disease. Int Rev Neurobiol 2017;134:827-58. http://dx.doi.org/10.1016/bs.im.2017.05.013.

[27] Sung S, Farrell M, Vijiaratnam N, Evans AH. Pain and dyskinesia in Parkinson's disease may share common pathophysiological mechanisms - An fMRI study. J Neurol Sci 2020;416:116905. http://dx.doi.org/10.1016/j.jns.2020.116905.

[28] Rabinstein AA, Shulman LM. Acupuncture in clinical neurology. The Neurologist 2003;9(3):137-48. http://dx.doi.org/10.1097/00127893-200305000-00002.

[29] Rajendran PR, Thompson RE, Reich SG. The use of alternative therapies by patients with Parkinson's disease. Neurology 2001;57(5):790-4. http://dx.doi.org/10.1212/wnl.57.5.790.

[30] Kundakci B, Kaur J, Goh SL, Hall M, Doherty M, Zhang W, et al. Efficacy of nonpharmacological interventions for individual features of fibromyalgia: a systematic review and meta-analysis of randomised controlled trials. Pain 2022;163(8):1432-45.

[31] Becker WC, Dorflinger L, Edmond SN, Islam L, Heapy AA, Fraenkel L. Barriers and facilitators to use of non-pharmacological treatments in chronic pain. BMC Fam Pract 2017;18(1):41. http://dx.doi.org/10.1186/s12875-017-0608-2.

[32] Wamelen DJV, Rukavina K, Podlewska AM, Chaudhuri KR. Advances in the pharmacological and non-pharmacological management of non-motor symptoms in Parkinson's disease: an update since 2017. Curr Neuropharmacol 2022. http://dx.doi.org/10.2174/1570159X20666220315163856 [Published online March 15].

[33] Deuel LM, Seeberger LC. Complementary therapies in Parkinson disease: a review of acupuncture, tai chi, Qi Gong, yoga, and cannabis. Neurother J Am Soc Exp Neurother 2020;17(4):1434-55. http://dx.doi.org/10.1007/s13311-020-00900-y.

[34] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.

[35] Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019.

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[36] Home - non-pharmacological intervention society. [Accessed November 7, 2022. https://www.npisociety.org/EN/].

[37] Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Die TIDieR Checkliste und Anleitung - ein Instrument für eine verbesserte Interventionsbeschreibung und Replikation. Gesundheitswesen 2016;78(3):175-88.

[38] Consort - Welcome to the CONSORT Website. [Accessed January 30, 2023. https://www.consort-statement.org/].

[39] Ninot G. Non-pharmacological interventions: an essential answer to current demographic, health, and environmental transitions. Springer International Publishing; 2021 [10.1007/978-3-030-60971-9].

[40] Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:14898.

[41] Skogar Ö, Borg A, Larsson B, Robertsson L, Andersson L, Andersson L, et al. "Effects of Tactile Touch on pain, sleep and health related quality of life in Parkinson's disease with chronic pain": a randomized, controlled and prospective study. Eur J Integr Med 2013;5(2):141-52.

[42] Schmitz-Hübsch T, Pyfer D, Kielwein K, Fimmers R, Klockgether T, Wüllner U. Qigong exercise for the symptoms of Parkinson's disease: a randomized, controlled pilot study. Mov Disord 2006;21(4):543-8. http://dx.doi.org/10.1002/mds.20705.

[43] Li J, Mi TM, Zhu BF, Ma JH, Han C, Li Y, et al. High-frequency repetitive transcranial magnetic stimulation over the primary motor cortex relieves musculoskeletal pain in patients with Parkinson's disease: a randomized controlled trial. Parkinsonism Relat Disord 2020;80:113-9.

[44] Myers PS, Harrison EC, Rawson KS, Horin AP, Sutter EN, McNeely ME, et al. Yoga improves balance and low-back pain, but not anxiety, in people with Parkinson's disease. Int J Yoga Therap 2020;30(1):41-8.

[45] Pérez de la Cruz S. Effectiveness of aquatic therapy for the control of pain and increased functionality in people with Parkinson's disease: a randomized clinical trial. Eur J Phys

Rehabil Med 2017;53(6):825-32. http://dx.doi.org/10.23736/S1973-9087.17.04647-0.

[46] Reuter I, Mehnert S, Leone P, Kaps M, Oechsner M, Engelhardt M. Effects of a flexibility and relaxation programme, walking, and Nordic walking on Parkinson's disease. J Aging Res 2011;2011:232473. http://dx.doi.org/10.4061/2011/232473.

[47] Gage H, Grainger L, Ting S, Williams P, Chorley C, Carey G, et al. Specialist rehabilitation for people with Parkinson's disease in the community: a randomised controlled trial [Internet]. Southampton (UK): NIHR Journals Library; 2014 [cité 20 sept 2023. Health Services and Delivery Research. Disponible sur : http://www.ncbi.nlm.nih.gov/books/NBK263782/].

[48] Allen NE, Moloney N, van Vliet V, Canning CG. The rationale for exercise in the management of pain in Parkinson's disease. J Park Dis 2015;5(2):229-39. http://dx.doi.org/10.3233/JPD-140508.

[49] Perez-Lloret S, Ciampi de Andrade D, Lyons KE, Rodríguez-Blázquez C, Chaudhuri KR, Deuschl G, et al. Rating Scales for Pain in Parkinson's disease: critique and recommendations. Mov Disord Clin Pract 2016;3(6):527-37.

[50] Moore RA, Derry S, Wiffen PJ. Challenges in design and interpretation of chronic pain trials. Br J Anaesth 2013;111(1):38-45. http://dx.doi.org/10.1093/bja/aet126.

[51] Pérez-de la Cruz S. Mental health in Parkinson's disease after receiving aquatic therapy: a clinical trial. Acta Neurol Belg 2019;119(2):193-200. http://dx.doi.org/10.1007/s13760-018-1034-5.

[52] Lei H, Toosizadeh N, Schwenk M, Sherman S, Karp S, Sternberg E, et al. A pilot clinical trial to objectively assess the efficacy of electroacupuncture on gait in patients with Parkinson's disease using body worn sensors. PLoS One 2016;11(5):e0155613.

[53] Toosizadeh N, Lei H, Schwenk M, Sherman SJ, Sternberg E, Mohler J, et al. Does integrative medicine enhance balance in aging adults? Proof of concept for the benefit of electroacupuncture therapy in Parkinson's disease. Gerontology 2015;61(1):3-14.

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[36] Home - non-pharmacological intervention society. [Accessed November 7, 2022. https://www.npisociety.org/EN/].

[37] Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Die TIDieR Checkliste und Anleitung - ein Instrument für eine verbesserte Interventionsbeschreibung und Replikation. Gesundheitswesen 2016;78(3):175-88.

[38] Consort - Welcome to the CONSORT Website. [Accessed January 30, 2023. https://www.consort-statement.org/].

[39] Ninot G. Non-pharmacological interventions: an essential answer to current demographic, health, and environmental transitions. Springer International Publishing; 2021 [10.1007/978-3-030-60971-9].

[40] Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:14898.

[41] Skogar Ö, Borg A, Larsson B, Robertsson L, Andersson L, Andersson L, et al. "Effects of Tactile Touch on pain, sleep and health related quality of life in Parkinson's disease with chronic pain": a randomized, controlled and prospective study. Eur J Integr Med 2013;5(2):141-52.

[42] Schmitz-Hübsch T, Pyfer D, Kielwein K, Fimmers R, Klockgether T, Wüllner U. Qigong exercise for the symptoms of Parkinson's disease: a randomized, controlled pilot study. Mov Disord 2006;21(4):543-8. http://dx.doi.org/10.1002/mds.20705.

[43] Li J, Mi TM, Zhu BF, Ma JH, Han C, Li Y, et al. High-frequency repetitive transcranial magnetic stimulation over the primary motor cortex relieves musculoskeletal pain in patients with Parkinson's disease: a randomized controlled trial. Parkinsonism Relat Disord 2020;80:113-9.

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