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Non‐pharmacological therapies for pain management in Parkinson's disease:

A systematic review

Article  in  Acta Neurologica Scandinavica · May 2021

DOI: 10.1111/ane.13435

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Received: 7 December 2020    Revised: 9 April 2021    Accepted: 11 April 2021

DOI: 10.1111/ane.13435

REVIEW ARTICLE

Non-­pharmacological therapies for pain management in

Parkinson's disease: A systematic review

Abdul Rehman Qureshi1,2 | Muhammad Khizar Jamal1  | Eraad Rahman1 |

Dion A. Paul1 | Yazan Shamli Oghli1 | Mohamed Thariq Mulaffer1 | Danial Qureshi3,4 |
Muhammad Affan Danish1 | Abdul Qayyum Rana1

1
Neurology, Parkinson's Clinic of Eastern
Toronto & Movement Disorders Centre,
Toronto, ON, Canada
2
Department of Health Research
Methods, Evidence, and Impact, McMaster
University, Hamilton, ON, Canada
3
Clinical Epidemiology Program, Ottawa
Hospital Research Institute, Ottawa, ON,
Canada
4
Bruyère Research Institute, Ottawa, ON,
Canada
Correspondence
Muhammad Khizar Jamal, Parkinson's
Clinic of Eastern Toronto, 1-­2060
Ellesmere Road, Toronto, ON M1H 2V6,
Canada.
Email: Mkj98@hotmail.ca
Among the various non-­motor symptoms of Parkinson's disease (PD), pain is often
cited as the most common and debilitating feature. Currently, the literature contains
gaps in knowledge with respect to the various forms of treatment available, particu-
larly non-­pharmacological therapies. Thus, the purpose of this systematic review is to
provide an examination of the literature on non-­pharmacological therapies for pain
in PD. We compared the findings of research articles indexed within various liter-
ature databases related to non-­pharmacological treatments of pain in PD patients.
Our review identified five major non-­pharmacological methods of pain therapy in
PD: acupuncture, hydrotherapy, massage therapy, neuromodulation, and exercise.
Treatments such as exercise therapy found a reduction in pain perception due to
various factors, including the analgesic effects of neurotransmitter release during
exercise and increased activity leading to a decrease in musculoskeletal rigidity and
stiffness. By the same token, hydrotherapy has been shown to reduce pain perception
within PD patients, with authors often citing a combined treatment of exercise and
hydrotherapy as an effective treatment for pain management. Multiple methods of
neurostimulation were also observed, including deep brain stimulation and spinal cord
stimulation. Deep brain stimulation showed efficacy in alleviating certain pain types
(dystonic and central), while not others (musculoskeletal). Hence, patients may con-
sider deep brain stimulation as an additive procedure for their current treatment pro-
tocol. On the other hand, spinal cord stimulation showed significant improvement in
reducing VAS scores for pain. Finally, although the literature on massage therapy and
acupuncture effectiveness on pain management is limited, both have demonstrated
a reduction in pain perception, with common reasons such as tactile stimulation and
release of anti-­nociceptive molecules in the body. Although literature pertaining to
non-­pharmacological treatments of pain in PD is sparse, there is copious support for
these treatments as beneficial to pain management. Further exploration in the form of
clinical trials is warranted to assess the efficacy of such therapies.

KEYWORDS
non-­pharmacological, pain, Parkinson's disease, systematic review

© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Acta Neurol Scand. 2021;00:1–17.  |

wileyonlinelibrary.com/journal/ane     1
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2      QURESHI et al.
1  |  I NTRO D U C TI O N
Parkinson's disease (PD) is a neurodegenerative disorder of the ner-
vous system resulting from the loss of dopaminergic neurons in the
substantia nigra pars compacta. While the etiology of PD remains
unknown, the disease has been shown to have both genetic and en-
vironmental influences. As there is no cure for PD, treatments are
often focused on controlling and reducing symptoms. Parkinson's
disease is most commonly characterized by motor symptoms such
as bradykinesia, rigidity, tremor, and postural instability.1 However,
patients who suffer from PD also experience many non-­motor symp-
toms (NMS) such as neuropsychiatric dysfunction, fatigue, sleep dis-
orders, autonomic dysfunction, sensory symptoms, and pain. Pain is
one of the most frequently reported debilitating symptoms among
those with PD and has been reported in both the early and late
stages of the disease. 2,3
Four different types of pain have been described in PD pa-
tients: musculoskeletal pain (due to parkinsonian rigidity, skeletal
deformity), radicular–­neuropathic pain (due to root lesion, focal or
peripheral neuropathy), dystonic pain (related to antiparkinsonian
medication), and akathisia (under off periods or drug-­induced).4
5
O'Sullivan et al. found that among all of the non-­motor symptoms,
pain was the most frequent, as it was evident in 53% of cases. The
prevalence of this symptom indicates a reason to analyze and im-
prove forms of pain management.
Improving pain treatment is crucial as PD is often associated
with multiple conditions. One such condition is its correlation for
depression in PD patients who report pain. Two groups comprising
of 120 patients with PD and 120 controls were tested using the
Pain Disability Index and Brief Pain Inventory. The authors found
a statistical correlation between pain severity, pain disability, and
depression among patients. 6 Therefore, PD patients experiencing
pain may have a further compromised quality of life due to psychi-
atric manifestations. A Korean study found that pain in PD patients
was correlated with the physical aspect (i.e., more severe motor
problems) of their quality of life, as compared to the group report-
ing no pain.7 There is additional support for this claim as Tinazzi
8
et al. found that the severity of pain in PD had a significant cor-
relation with the severity of motor complications. Furthermore,
researchers have found that pain sensitivity seems to be higher in
PD patients than in controls, especially as the disease progresses.9
All of these findings indicate that improper management of pain in
patients may cause faster progression of the PD, suggesting that
pain should be an essential focus in the overall management of PD
patients.
Many knowledge gaps remain in the treatment of pain in PD.
Pain and other non-­m otor symptoms are often under-­d iagnosed
in patients, and there is difficulty in separating PD-­r elated pain
2
from other types of pain ; this causes many pain symptoms to
be poorly treated in patients. The effectiveness of current pain
management protocols, whether they be pharmacological, non-­
pharmacological, or a combination, is variable and incomplete. 2
This inconclusiveness suggests that further studies are warranted
to understand both pharmacological and non-­p harmacological
therapies. In particular, few studies have specifically reviewed
the non-­p harmacological methods in managing pain in PD pa-
tients.1,2 Thus, this review's purpose was to highlight the com-
plementary procedures and therapies available for managing pain
in PD patients, as identified in current literature, and to provide
suggestions for pain treatment.
2  |  M ATE R I A L S A N D M E TH O DS
A literature search through MEDLINE, AMED, EMBASE, PsycINFO,
CINAHL, and CENTRAL databases was conducted, with a temporal
span from inception to present. Major search terms used included
“Parkinson's,” “pain management,” “hydrotherapy,” “exercise,” “acu-
puncture,” “massage,” “aquatic physical therapy,” “neuromodulation”
and “music.” Articles meeting the following criteria were eligible for
inclusion:
1. Participants of the study have a diagnosis of PD.
2. An interventional study using a non-­pharmacological therapy on
PD patients.
3. A categorical or quantitative measure of pain is reported in the
study.
Manual searches of reference lists of included studies were also
performed to identify further eligible studies. No exclusion was con-
sidered based on the language or year of the article. Two indepen-
dent raters screened articles for their title and abstract, and after
that the full texts for study eligibility. Cohen's kappa (κ) was calcu-
lated to determine agreement for study eligibility.
Data extracted from eligible studies included lead author and
year, study design, intervention, funding source, country, assess-
ment instrument for pain, sample size, age, gender, disease du-
ration of PD, and lost or missing data. A detailed assessment of
pain induced subsequent extraction of statistical significance for
pre-­p ost-­m easurements of pain, classification as a primary or sec-
ondary outcome, minimal reduction of pain (%), and any additional,
relevant information to the aforementioned categories. A minimal
reduction in patient-­reported pain by 20% was considered as the
threshold for a minimally important difference (MID).10 The data
that support the findings of this study are available in Tables 1–­4
of this article.
Risk of bias (ROB) assessment methods were utilized that
were specific to each study type. In particular, the ROB criteria
compiled by Murad et al.11 was used for case reports, the Risk
of Bias in Non-­R andomized Studies of Interventions (ROBINS-­I)
by Sterne et al.12 was used for interventional observational stud-
ies, and the ROB criteria by Higgins et al.13 was used for random-
ized controlled trials (RCTs). Two independent raters evaluated
each study for ROB. The intraclass correlation coefficient (ICC)
was calculated for each ROB assessment to determine inter-­r ater
agreement.
QURESHI et al.
3  |   R E S U LT S
3.1  |  Search
Twenty-­nine studies were eligible for full-­text screening, of which
five articles were excluded due to the absence of PD patients in
the study sample,14–­18 one article was excluded for lacking an inter-
vention19 and three articles did not report any pain measure. 20–­22
Consequently, 20 studies were included in the quantitative and
qualitative analysis. Agreement for study eligibility between two in-
dependent raters was strong (κ = 0.821, p = .001).
3.2  |  Study characteristics
These 20 studies spanned five major techniques in the non-­
pharmacological management of pain in PD, which include massage
23–­25 26,27
therapy, acupuncture (non-­electrical or electrical
ercise therapy29,30 (including yoga31), aquatic therapy,32,33 or neu-
romodulation34–­42 (Table 1). The eligible articles consisted of three
case reports or case series, eight RCTs, and nine non-­randomized
interventional studies. The geographical distribution of articles
comprised East Asian (seven articles), North American (five articles),
European (seven articles), and South American (one article).
3.3  |  Outcome assessment
Twelve studies assessed pain as a primary outcome, while the re-
maining eight studies assessed pain as a secondary outcome. Among
the studies assessing pain as a primary outcome, seven studies
found a statistically significant effect (p  <  .05) of the intervention
comparing baseline to final follow-­up. 21,29,34,36,37,41 Among the stud-
ies assessing pain as a secondary outcome, only one study found
a statistically significant effect of the intervention relative to con-
trol when considering baseline and follow-­up measurements. 25
A minimum of 20% reduction in pain (MID) comparing baseline to
23–­25,27,28,32–­42
follow-­up was met by 17 studies ; one of these studies,
which used aquatic therapy as an intervention, met this MID in its
first follow-­up (8 weeks, 33%), but no longer met the MID in its sec-
ond and final follow-­up (16 weeks, 7%).33 One study did not provide
an accompanying follow-­up measurement of pain with its baseline
measurement, 29 and another study intended to assess pain though it
did not report a baseline or follow-­up measurement of pain. 26
3.4  |  Risk of bias
Inter-­rater agreement on ROB assessment for each study category
was moderate to strong (case reports: ICC = 0.768, p < .0001; RCTs
–­ ICC  =  0.783, p  <  .001; non-­randomized studies: ICC  =  0.912,
p < .0001). Overall, selection bias from reporting bias from selective
reporting was low in all RCTs (Table 2). Selection bias from random
|
      3
sequence generation was low in all of the studies except 1 study
where it was high (low, 8%; high, 92%). The majority of the RCTs
had a low risk of selection bias from a lack of allocation concealment
(low, 70%; high, 30%) and performance bias from issues with blind-
ing of participants and personnel (low, 38%; high, 62%). Most RCTs
had a low risk of detection bias related to issues with blinding of
outcome assessment (low, 69%; high, 31%) and attrition bias due to
incomplete outcome data (low, 85%; high, 15%).
For the ROB assessment of non-­r andomized interventional
(N-­R I) studies, 53% had a low risk of bias due to classification of
interventions, 100% had a low risk of bias due to deviations from
intended interventions, and 92% had a low risk of bias due to miss-
ing data. 53% of the studies had a low risk of bias due to selection
of participants into the study, 38% had a medium risk, and 8% of
the studies had a serious risk of bias. For bias due to selection of
the reported results, 23% had low bias, 23% had moderate bias,
38% had serious bias, and 15% had critical bias. The majority of
28
), ex- the studies (54%) had a serious risk of bias due to confounding,
while 38% had a moderate risk, and only one study was at low risk
of confounding bias (8%). A serious risk of bias in the measurement
of outcomes was found for the majority of the studies (62%), while
23% purported a moderate risk of outcome measurement and 15%
had a low risk. The overall rating of the NR-­I studies was either a
moderate risk of bias (23%), a serious risk of bias (62%), or a critical
risk of bias (15%) (Table 3).
In terms of the case reports (CARs), all (3/3) reported an agree-
ment for the selection of participants that represent the whole ex-
perience of the investigator or center. Although the exposure was
adequately ascertained in all CARs, only 1 (33%) adequately affirmed
the outcome. In two out of the three studies (67%), the alternative
causes to explain the result were not ruled out, a dose–­response ef-
fect did not exist, and follow-­up was long enough (at least 5 weeks)
for the outcome to occur. There was no challenge–­rechallenge phe-
nomenon in any CAR. In all of the CARs (3/3), there was a detailed
description that was adequate to allow replication of the study or to
enable clinicians to make inferences related to their own practice. An
overall assessment of the methodological quality was of low quality
for all of the CARs (3/3) (Table 4).
3.5  |  Exercise in pain management
The popular recommendation currently supports exercise as part
of pain reduction treatment plans in a variety of conditions. Many
pathophysiological reasons as to why this may be the case have
been examined in patients. One supporting finding points to the
possible analgesic properties of dopamine; activation of D2 recep-
tors was found in pain inhibition of the nociceptive jaw reflex.43–­45
Since exercise is found to increase dopamine levels in rodents,46,47
the anti-­n ociceptive properties of exercise may be partly due
to the extra availability of neurotransmitters, which inhibit the
perception of pain. Subsequent studies on rodents have indi-
cated that exercise prevents the age-­related loss of hypothalamic
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4      QURESHI et al.

TA B L E 1  Characteristics of included studies*

Lead author and Non-­pharmacological

year Study design intervention Funding source Country Assessment of pain severity

Donoyama 2012 Case series Massage Tsukuba University of Japan VAS

Technology

Donoyama, 2014 Before–­after Anma massage Tsukuba University of Japan VAS

Technology
Miyahara 2018 Single-­blinded Therapeutic Thai Massage National Research Council Thailand VAS
RCT of Thailand, Chula
Research Scholar of the
Ratchadaphiseksomphot
Endowment Fund, and
Chulalongkorn Academic
Advancement Fund
Shulman 2002 Non-­blinded, non-­ Acupuncture NR USA N/A (not clear)
randomized
pilot

Iseki 2014 Case report Acupuncture NR Japan VAS

Toosizadeh 2015 Double-­blinded, Electroacupuncture National Institute on Aging, and USA VAS
pilot RCT Arizona Center on Aging
Rosarion 2018 Case report Exercise therapy NR USA VAS
Perez De La Cruz Single-­blinded Aquatic therapy NR Spain VAS
2017 RCT

Poliakoff 2013 Single-­blinded, Gym training Parkinson's UK UK PDQ -­BIPQ

pilot
RCT
Volpe 2017 Single-­blinded, Aquatic therapy None Italy NR
pilot RCT

Ni 2016 Single-­blinded, Yoga None USA NR

pilot RCT

Kim HJ Comparative Subthalamic nucleus deep N/A Korea Ordinal scale (0–­10 range) (for
brain stimulation (STN 7 body parts)
DBS)
Pellaprat J Prospective Subthalamic nucleus deep N/A France McGill Pain Questionnaire e
cohort brain stimulation (STN Pain Questionnaire of Saint
DBS) Antoine (MPQ-­Q DSA)

Dellapina E 1. Chronic cohort Subthalamic nucleus deep Abbott, Addex, Boehringer France Unofficial Questionnaire
sub-­study brain stimulation (STN Ingelheim, Eisai, developed by Toulouse
2. Acute RCT, DBS) GlaxoSmithKline, Impax Hospital, VAS
double-­blind Pharmaceuticals, Lundbeck,
sub-­study Merck Serono, Movement
Disorders Society, Novartis,
Oxford Biomedica,
Schering-­Plough, Servier,
Teva Neuroscience, UCB,
and XenoPort
Loher TJ Prospective Pallidal deep brain N/A Switzerland Ordinal scale (0–­10 range) (for
stimulation 6 body parts)
QURESHI et al.       5 |

Disease duration, years,

Sample size1, n Age, years, mean (SD) Gender, men % mean (SD) Lost/missing data, n
Treatment/control Treatment/control Treatment/control Treatment/control Treatment/control Study duration

N = 10 (no controls) 69.6 (7.7) (no controls) 60% (no controls) Stages 2 to 4 (H&Y None 30-­min massage session
Scale), duration from
onset: 1–­19 years
N = 21 (all received 64.43 (8.39) 57.14% Stages 1 to 4 (H&Y Scale) N = 6 did not receive 2-­month intervention
treatment) control period
N = 60 66.37 (7.32)/64.10 63.3%/46.7% 8.53 (4.73)/9.17 (7.76) NR 4-­week screening
30/30 (10.83) period and 3-­week
interventional period

N = 20 68 60% 8.5 N/A 7 patients received 10

treatments in 5 weeks.
Next 13 patients
received 16 treatments
in 8 weeks
N = 1 81 0% 3 None 3 weeks
N = 15 (10/5) 71.1 (3.0)/71.4 (3.9) 60%/40% NR N/A 3 weeks

N = 1 85 100% Not listed N/A 5 weeks

N = 30 66.80/67.53 NR Disease in stages 1 to NR 10-­week intervention and
15/15 3 (Hoehn and Yahr 1-­month follow-­up
Scale)
N = 22 68.8/66.6 75%/80% 7.9/4.58 Started -­16/16 10-­week and 20-­week
12/10 follow-­up

N = 30 70.6 ± 7.8 (59–­ 9/15 male -­10/15 9.4 ± 7.5 (2–­32)/9 ± 7.0 13/11 (water/ 8-­week treatment and
15/15 (water/ 84)/70 ± 7.8 male (3–­25) non-­water-­based) follow-­up 8-­weeks after
non-­water-­based) (51–­82) treatment. 16-­weeks
in total
N = 27 71.2 (6.5)/74.9 (8.3) 11/15 male -­6/12 6.9 (6.3)/5.9 (6.2) 27 originally. 2-­week pre-­test, 12-­week
15/12 male 15/12 (control intervention, and 2-­
treatment) week post-­test
Analyzed 13/10
N = 29 (no controls) 59 (7.7) (no controls) 48% (no controls) 9.9 (4.6) (no controls) N/A 3-­day pre-­test, 3-­month
follow-­up, intervention
period N/A
N = 58 (no controls) 60.3 (7.8) (no controls) 64% (no controls) 12.3 (3.8) (no controls) N/A Evaluated 1 week prior
to intervention and
12 months following
intervention,
intervention period N/A
N = 16 65.1 (5.0)/61.8 (7.6) 50% (overall) 12.4 (2.6)/13.1 (2.9) N/A 1. Treatment for at least
8/8 3 months, assessment
prior to treatment, and
at least 3 months after
2. 3 h of treatment, and
a post-­evaluation after
12 h

N = 16 (no controls) 64.9 (7.7) (no controls) 63% (no controls) 18.2 (7.1) (no controls) N/A Follow-­up assessment
3–­5 days, 3 months, and
1 year after surgery

(Continues)
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6      QURESHI et al.

TA B L E 1  (Continued)

Lead author and Non-­pharmacological

year Study design intervention Funding source Country Assessment of pain severity

Jung YJ Comparative Subthalamic nucleus deep A101273 from the Korea Health Korea Ordinal scale (0–­10 range) (for
brain stimulation (STN Technology R&D Project, 7 body parts)
DBS) Ministry of Health &
Welfare, Republic of Korea

Kim HJ Comparative Subthalamic nucleus deep Seoul National University Korea Ordinal Scale (0–­10 range) (for
brain stimulation (STN Hospital research grant 7 body parts)
DBS)

Marques A Crossover Subthalamic nucleus deep Programme Hospitalier France Patient-­reported pain
double-­blind brain stimulation (STN de Recherche Clinique threshold (thermal and
randomized DBS) (PHRC) 2006, no. 050986, mechanical stimulation)
trial Fondation pour la recherche
Médicale
Cury RG Prospective Subthalamic nucleus deep Supported by FAPESP Brazil Brief Pain Inventory, BPI
brain stimulation (STN (Fundação de Amparo à
DBS) Pesquisa do Estado de São
Paulo) 2010/19392, and
Pain Center Research Fund
from the Department of
Neurology, University of
São Paulo, Brazil
Krishnan VC Prospective Spinal cord stimulation N/A USA VAS, Unified Parkinson's
Disease Rating Scale,
Self-­Rating Depression
Scale, Hamilton Depression
Rating Scale, Profile of
Mood State, 10-­meter
walking test, and the Timed
Up and Go (TUG)
*
Abbreviations: H&Y, Hoehn and Yahr; NR, not reported; PDQ-­39, Parkinson's Disease Questionnaire Item 39—­Pain Score; PDQ-­BIPQ, Parkinson's
Disease Questionnaire–­Brief Illness Perception Questionnaire; RCT, randomized controlled trial; SCOPA, Scales for Outcomes in Parkinson's
disease; SPES, Short Parkinson's Evaluation Scale; VAS, visual analogue scale.

oxytocinergic neurons.48 Since oxytocin has been found to de-
crease pain, it can be said that this release during exercise indi-
rectly reduces pain.49
Furthermore, adenosine (a product from the breakdown of the
energy molecule adenosine triphosphate [ATP]) released during
exercise has been shown to have anti-­n ociceptive properties.43
Research has found adenosine receptor agonists to be helpful with
neuropathic pain (NP)50 and chronic persistent pain. 51 This may
partly be attributed to its ability to decrease inflammation and in-
flammatory cytokines. Allen et al.43 also suggest that exercise may
be especially beneficial for relieving the musculoskeletal (MSK)
component of pain in PD patients. Since MSK pain in PD patients
is thought to come from rigidity, muscle wasting, akinesia, and
dystonia, exercise—­w hich addresses these symptoms—­may relieve
the pain associated with MSK. Furthermore, stiffness, postural de-
formities, and overall lack of PD patients' movement are thought
to exacerbate or bring about pain.43 While studies investigating
exercise as a form of pain management in PD patients are limited
in the literature, an article that examined the effect of postural
exercises on six patients with PD found that after 10 sessions of
90-­min exercise therapy, a decrease in back pain was reported. 52
An article by Poliakoff et al. (2013) also found exercise to improve
fitness and motor initiation. The study revealed that there was
an overall improvement in corticomotor functioning and that re-
sponse times improve immediately following exercise. Feedback
on the intervention revealed a favorable outcome, with 79% of the
participants' comments being positive and 21% of the comments
related to barriers and difficulties. 30 These difficulties varied be-
tween participants. A few participants got cramps and pain from
the program; one participant noted how attending the sessions felt
distressed over how much less he could do than previously, and an
older participant had some cognitive difficulties. One article fo-
cused on a novel avenue of physical exercise in yoga. In particular,
this was a power yoga program using Vinyasa style, specifically
designed to target bradykinesia by using high-­speed movement
and to target muscle weakness by using strengthening postures. 31
The yoga group generated a significant decrease in the upper (4.5
points) and lower limb (2.5 points) bradykinesia score, and a large
effect size compared with the control group (upper limb: g = −1.75;
lower limb: g = −1.11, p < .001). With rigidity, the yoga group had
QURESHI et al.       7|

Disease duration, years,

Sample size1, n Age, years, mean (SD) Gender, men % mean (SD) Lost/missing data, n
Treatment/control Treatment/control Treatment/control Treatment/control Treatment/control Study duration

N = 24 (no controls) 59.1 (7.6) (no controls) 63% (no controls) 18.0 (3.8) (no controls) N/A Pre-­operative evaluation
over a period of
3 days, post-­operative
evaluation 8 years after
surgery
N = 21 (no controls) 58.3 (7.9) (no controls) 38% (no controls) 10.6 (4.0) (no controls) N/A Pre-­operative evaluation
for 3 days, post-­
operative evaluation
performed at 3 and
24 months
N = 19 (no controls) 62.3 (5.7) (no controls) N/A 13.2 (2.8) (no controls) N/A Intervention period for
14 days

N = 41 (no controls) 60.0 (10.4) (no 66% (no controls) 15.0 (7.6) (no controls) N/A The patients were
controls) prospectively evaluated
before and 12 months
after surgery

N = 15 (no controls) 74 (5.2) (no controls) N/A (no controls) 17 (8.7) (no controls) N/A N/A

both a reduction in overall rigidity score (2.6 points) and a larger
effect size (g = −.64, p = .001). Muscle strength also improved fol-
lowing training (p < .05). In conclusion, 3 months of this program
displayed a reduction in limb bradykinesia and joint rigidity, in-
creased muscle strength and power, and improved self-­reported
quality of life in PD patients at Hoehn and Yahr stage I, II, or III. The
yoga program proved to be well-­tolerated by patients and resulted
in an exceptional level of exercise adherence. 31 Furthermore, even
simple exercises such as walking have shown a reduction in pain
in PD patients. 53,54 Rosarian (2018) reported that after 5  weeks
of physical/exercise therapy, an 85-­year-­old PD patient showed
a significant reduction in back pain. 29 There is accumulating ev-
idence for the benefits of physical therapy in PD with respect
to parameters that include walking speed, stride length, and the
number of falls. Furthermore, fatigue is a well-­k nown symptom
of PD. Supplementing pharmacological interventions with exer-
cise to reduce pain is an area of active research. However, Elbers
et al. 55 traversed beyond the usual investigations of exercise in
pain management and probed the therapeutic benefits of exer-
cise in reducing fatigue. Minor trends were uncovered favoring
exercise, but these proved to be insignificant. 55–­57 Exercise is a
reliable adjunct for pain reduction, though may not be therapeutic
in attenuating fatigue.
3.6  |  Hydrotherapy and aquatic physical therapy in
pain management
Hydrotherapy, in the form of aquatic physical therapy, has been
introduced in managing pain in PD patients. Ai Chi consists of a
series of aquatic exercises that involve a combination of move-
ment via the upper and lower limbs and the trunk in a slow, co-
ordinated rhythm. 32 One article examined 15 PD patients in a
10-­week Ai Chi program to determine whether there were any
changes in the pain visual analogue scale (VAS) after hydro-
therapy. 58 The article found that patients reported significant
improvement in their symptoms of pain, supporting the use of
aquatic therapy in the management of pain in PD. Another article,
whose aim was to identify the effectiveness of aquatic therapy
on pain perception, separated 30 PD patients into two treatment
 |
8     

TA B L E 2  Risk of bias assessment for randomized controlled trials (RCTs)

Random sequence Allocation Blinding of participants and Blinding of outcome Incomplete Selective
generation (selection concealment personnel (performance assessment (detection outcome data reporting Overall
Study name bias) (selection bias) bias) bias) (attrition bias) (reporting bias) Other bias bias

Miyahara 2018 Low High High Low Low Low Low High
Ni 2016 Low High High High Low Low Low High
Perez de la Cruz 2016 Low High High Low Low Low Low High
Poliakoff 2013 Low High High High High Low Low High
Toosizadeh 2015 Low Low Low Low Low Low Low Low
Volpe 2017 Low Low High Low High Low Low High
Sagrario Pérez-­de la Low Low Low High Low Low Low High
Cruz 2019
Pickut et al. 2015 Low Low Low Low Low Low Low Low
Carl-­Johan Törnhage Low Low Low Low Low Low Low Low
et al. 2013
Stallibrass et al. 2002 Low Low High Low Low Low Low High
Ires et al. 2017 Low Low High Low Low Low Low High
Dellapina et al. 2012 High Low High High Low Low Low Low
Marques et al. 2013 Low Low Low Low Low Low Low Low
QURESHI et al.
 QURESHI et al.

TA B L E 3  Risk of bias assessment for non-­randomized interventional studies

Bias in selection of Bias in

Bias due to participants into the Bias in classification Bias due to deviations from Bias due to measurement Bias in selection of the
confounding study of interventions intended interventions missing data of outcomes reported result(s) Overall bias

Donoyama et al. 2012 Serious Moderate Low Low Low Serious Moderate Serious
Donoyama et al. 2014 Moderate Low Low Low Low Serious Moderate Serious
Shulman et al. 2002 Moderate Moderate Low Low Low Moderate Low Moderate
Dibble et al. 2006 Low Moderate Moderate Low Low Low Low Moderate
Conradsson et al. Moderate Moderate Serious Low Low Moderate Moderate Serious
2014
Paolucci T et al. 2014 Moderate Moderate Moderate Low Low Moderate Low Moderate
Kim et al. 2008 Serious Low Low Low Low Serious Serious Serious
Pellaprat et al. 2014 Serious Low Serious Low Low Serious Critical Critical
Dellapina et al. 2012 Serious Serious Serious Low Low Serious Serious Serious
Loher et al. 2002 Serious Low Low Low Low Serious Serious Serious
Jung et al. 2015 Serious Low Low Low Moderate Serious Serious Serious
Kim et al. 2012 Serious Low Low Low Low Serious Critical Critical
Cury et al. 2014 Moderate Low Serious Low Low Low Serious Serious
|
      9
 |
10      QURESHI et al.

TA B L E 4  Risk of bias assessment for case reports

Iseki Rosarion Elkins et

Domains Leading explanatory questions 2014 2018 al. 2013

Selection 1. Does the patient(s) represent(s) the whole experience of the investigator Yes Yes Yes
(center) or is the selection method unclear to the extent that other patients
with similar presentation may not have been reported?
Ascertainment 2. Was the exposure adequately ascertained? Yes Yes Yes
3. Was the outcome adequately ascertained? No No Yes
Causality 4. Were other alternative causes that may explain the observation ruled out? No Yes No
5. Was there a challenge/rechallenge phenomenon? No No No
6. Was there a dose–­response effect? No Yes No
7. Was follow-­up long enough for outcomes to occur? No Yes Yes
Reporting 8. Is the case(s) described with sufficient details to allow other investigators to Yes Yes Yes
replicate the research or to allow practitioners make inferences related to
their own practice?
Overall judgment of methodological quality Low Low Low

regimes, one consisting of Ai Chi and another conducted on dry
land.15 The researchers again found a statistically significant dif-
ference in pain perception among the patients who completed the
Ai Chi program, with these patients reporting lower pain vs the
participants undergoing the program on dry land. Aquatic therapy
improves the dynamic balance and gait speed of individuals. Post
hoc analyses from Volpe et al. (2017) showed that cervical flex-
ion was significantly reduced in patients who received the water
intervention at 8 weeks (p = 0.004) and 16 weeks (p = 0.001). 29
Moreover, relative to the non-­w ater-­b ased intervention, dorsal
flexion was reduced immediately after completing the water-­
based intervention (p  =  0.002). However, post hoc analyses did
not show significant differences between either intervention for
29
dorsal flexion at 8 weeks or 16 weeks (p > 0.05). Volpe et al.
(2017) also identified a significant improvement of symmetry only
in the water-­b ased group (p  =  .002), and no significant changes
for the land-­b ased group (p  =  .95) at the end of the treatment.
Other studies have also shown improvements in postural stability
and fewer falls in patients with neurological disorders compared
with patients performing therapy on dry land. Pérez-­d e la Cruz
et al. (2016) identified a decrease in dystonia and dyskinesia and
improvement in postural deformities, as well as significant differ-
ences in the pain variables post-­t reatment for the experimental
group (p  <  .001). In the control group, improvements were only
seen on the VAS, which was less significant than the changes
found in the experimental group (p  =  .006). 32 It has been sug-
gested that postural deformities in PD could also be related to a
deficit in somatosensory integration. Thus, it can be speculated
that external stimulation by water resistance can favor a specific
modulation of proprioceptive afferents. A water environment can
increase proprioceptive inputs to the immersed body leading to
a better body alignment, which yields better results relative to
dry land. Finally, this unique treatment option with its combined
benefits of exercise and hydrotherapy may provide appreciable
results in pain management.
3.7  |  Massage and pain management
Massage is a common adjunctive therapy used by patients with PD.23
There is evidence in the literature that points to massage therapy being
beneficial in the management of pain, such as in the reduction in lower
back pain by progressive muscle relaxation therapy.14 Massage therapy
may also be easily incorporated into an acute healthcare setting, as re-
searchers found decreased reported pain when hospital patients were
provided such sessions.15 However, there are limited data on the ef-
fect that massage therapy would have on specifically alleviating pain
in PD patients. A single-­blinded RCT using Thai massage therapy in 60
PD patients found a significant improvement in the VAS score from
6.43 (1.46) to 2.70 (1.12) in the intervention group (n = 30) and a 0.20-­
point improvement in the control group.25 One study using a before–­
after design assessed the use of a Japanese massage therapy known
as Anma massage in reducing pain in PD patients.24 The results indi-
cated a reduction in muscle stiffness (p = .001), difficulty in movement
(p = .0019), and shoulder pain (p = .0047) after a single 40-­min session
of Anma massage. Another study conducted by Suoh et al.20 further
demonstrated that Anma massage can reduce shoulder pain associated
with rigidity, though it may also reduce muscle tone. Further studies
show that both therapeutic and deep tissue massages, which contin-
ued for 10 days (30 min each day), contributed to improving persistent
lower back pain.16 A case report further revealed that massage therapy
reduced rigidity (an often-­painful symptom in PD patients), though only
temporarily.19 Kim et al.59 conducted interviews for PD patients' past
and current use of contemporary and alternative medicine and found
that four out of seven patients (57.1%) reported that massage therapy
had a positive effect on pain and stiffness in their muscles.
Complementary and alternative medicine improved PD-­related
symptoms for six patients, and a mild therapeutic improvement was
reported by 31 patients. A study utilizing interviews measured atti-
tudes toward the use of analgesics for 46 patients with neuromuscular
disorders who reported pain, with 31 of those patients having PD.60
The 46 patients reported an average pain intensity in the preceding
QURESHI et al.
week as 4.1 (standard deviation = 1.9) out of a scale of 10 (p = .05). Of
the 21 patients who used massage to deal with pain, 19 (90%) patients
reported that it was effective. In this study, it was not made clear as to
how many PD patients used massage as a method to ease their pain.
An investigation into whether tactile stimulation provided a reduction
in pain perception in PD patients also demonstrated a slight improve-
ment in chronic pain in one article.61 Also, a significant reduction in
chronic pain was found in another article.61 Overall, the evidence
supporting the use of massage therapy in pain management warrants
further examination into its long-­term effects for PD patients.
3.8  |  Acupuncture and pain management
Acupuncture is a technique whereby specific locations on the body
are stimulated, usually by insertion of long needles, which are then
moved by hand or with the use of electricity. Acupuncture, along
with massages, is one of the more commonly used alternative medi-
cines by PD patients. 26 The mechanism in which acupuncture is pro-
posed to relieve pain stems from the slight injury it causes in the
62
skin during insertion. This damage causes the release of ATP, which
may be later converted into adenosine. Since these molecules are
both known to exhibit anti-­nociceptive abilities, the perception of
pain may decrease when they are released. An article that analyzed
whether electroacupuncture would be beneficial for treatment in PD
found a reduction in reported pain (though not statistically signifi-
cant), as well as a statistically significant reduction in rigidity by 48%
28
(p < .02). Since rigidity has been known to cause pain in PD, this
finding indicates the potential for electroacupuncture in pain relief in
PD. A case study on an older woman diagnosed with PD and excruci-
ating leg pain found that doing classical acupuncture and electroacu-
puncture five times a week for 2 weeks immensely dropped the VAS
score from 70 to 16 mm on her right leg.15 The VAS score dropped
from 45 to 5 mm on her left leg. A study conducted in Korea by Kim
59
et al. demonstrated that 23 out of 59 PD patients (40.0%) reported
a positive therapeutic effect of acupuncture therapy on muscle pain
and stiffness. Another study found that 78.3% of patients using acu-
18
puncture considered it effective. However, 61.1% of patients re-
ported that the duration of effect was limited, such that the effects
disappeared during therapy or less than 4 weeks after therapy.
3.9  |  Neuromodulation
Neuromodulation is a practice that refers to the stimulation, inhibi-
tion, or modification of the central, peripheral, or autonomic nerv-
ous system through electrical or chemical means.
3.9.1  |  Deep brain stimulation
Deep brain stimulation (DBS) is a procedure that involves the stimu-
lation of specific regions of the brain via the insertion of electrodes.
|
      11
Evidence suggests that stimulation of particular regions within the
basal ganglia (BG), such as the subthalamic nucleus (STN) and the
globus pallidus (GP), can have beneficial outcomes in pain manage-
ment of PD patients. Circuitry within the BG is known to process
sensory information such as pain.34,37–­40,42 Patients suffering from
PD may exhibit impaired BG functioning, and thus, by modulating
BG circuitry via DBS, pain processing can be managed. To assess
this effectiveness on motor-­related pain, it is essential to distinguish
between the ON and OFF states. The ON state entails that phar-
macological intervention is utilized for easing motor symptoms of
PD. In contrast, the OFF state indicates the re-­emergence of such
symptoms in the absence of such interventions. For our analysis, we
hope to exclusively address DBS impact among patients during their
OFF state. From the studies assessed, various types of pain were
investigated. A distinction was made between acute and long-­term
effects of DBS, and certain regions of the body experiencing pain
were also considered.
Looking at general overall pain, one study found a signifi-
cant decrease in pain symptoms at 12  months after unilateral
(p = .0009) and bilateral DBS (p = .014). 38 In another study, affec-
tive pain (described as tiring exhausting, fearful, obsessive, sick-
ening, irritating, etc.) and sensory pain (described as throbbing,
sharp, stabbing, nagging, burning, etc.) were both found to be sig-
nificantly reduced in severity at 12 months after DBS (p < .0001
and p  =  .03, respectively). Furthermore, pain in the lower limbs
(p = .02) and head or neck (p = .001) regions was significantly re-
duced. 36 Moving toward more specific forms of pain, dystonic pain
(associated with movements and postures) was found to be the
most responsive to DBS, with reports of a 100% improvement rate
at 3 months and reports of significant improvement at 12 months
post-­operation assessment (p < .001). 35,40,42 Central pain (associ-
ated with burning and scalding) was also quite responsive to DBS,
with 92% improvement at 3 months, 44% at 8 years, and 54% at
3  months. 35,39,40 Radicular nerve pain (localized to the nerve or
root area) was responsive at a rate of 63% at 3  months, 55% at
8 years, and 17% at 3 months. 35,39,40 Musculoskeletal pain (associ-
ated with stiffening and cramping) was noted as the least respon-
sive among certain studies, 14% at 3 months, 29% at 8 years, and
27% at 3  months. 35,39,40 However, one study that analyzed the
significance found a significant difference in musculoskeletal pain
intensity between pre-­DBS and 12 months post-­DBS (p < .001).42
Several studies reported that pre-­DBS pain was most prevalent in
the lower back area and lower limbs, which also happen to be the
least responsive to DBS. 35,39,40,42 Given that DBS can have a long-­
term impact on pain, we now mention the acute effect that DBS
can have on the pain threshold. In both of the studies we consid-
ered, thermal stimulation was utilized to assess the degree of pain
threshold, and one study also included mechanical stimulation. 37,41
After undergoing STN DBS, PD patients who were explicitly suf-
fering from central NP (described as tingling, burning, numbness,
etc.) experienced a significant increase in their pain threshold level
when assessed at 3 months (p = .03). 37 Furthermore, PD patients
suffering from central NP exhibited a significantly lower pain
 |
12      QURESHI et al.
threshold than pain-­free PD patients (p  =  .02). 37 Similar findings
were evident in the next study, albeit only for mechanical pain
threshold, in which patients exhibited an increased pain threshold
at 1-­week assessment (p  =  .02).41 Lastly, the number of patients
reporting pain was significantly reduced at 1-­week assessment
41
(p  =  .0009). Note that such patients did not exhibit central NP
features as in the first study.
3.9.2  |  Spinal cord stimulation
Another method that can be used to treat both pain and motor
symptoms of PD is spinal cord stimulation (SCS). Previous studies
have shown that SCS mediates pain relief via stimulation of the
large non-­nociceptive methylated fibers on the peripheral nerve
(A-­β fibers).34 This in turn leads to inhibition of the small nociceptive
projection (A-­δ and C) in the dorsal horn.34 Additionally, SCS may
lead to the release of neurotransmitters involved in neuromodula-
tion, such as GABA, substance-­P, and serotonin.34 The patients in
this study had percutaneous electrodes implanted in the epidural
space in the spine at the thoracic or the cervical level and received
either continuous tonic stimulation, continuous burst stimulation
(40  Hz, 500  Hz, 1000  μs), or cycle mode (on time of 10–­15  s, off
time of 15–­3 0 s) with burst (40 Hz, 500 Hz, 1000 μs).34 Also, of the
15 patients, eight had undergone DBS before initiation, while seven
34
had no DBS before initiation. It was found that all patients in the
study reported significant improvement in VAS pain scores follow-
ing SCS implantation with a mean reduction of 59% (two-­t ailed t
34
test, p < .005). Patients who had received DBS before SCS experi-
enced a 61% reduction (two-­t ailed t test, p < .0001), while patients
who had not received DBS prior experienced a 57% reduction (two-­
tailed t test, p < .0007).34 Also, this study found within-­group differ-
ences using multiple forms of stimulation techniques; patients who
received cycling burst stimulation had an average of 67% reduction
in VAS scores, and a 48% reduction in VAS scores was seen in pa-
tients who received the continuous burst stimulation. 34 In addition,
a 10-­meter walk test was performed in order to assess improvement
34
of a motor symptom known as parkinsonian gait. 73% of all pa-
tients improved in the 10-­meter walk, with an average improvement
of 12% (two-­t ailed paired t test, p = .003).34 Finally, 64% of patients
showed a clinically significant improvement in Timed up and Go
completion time, with an average improvement of 21% (two-­t ailed
paired t test, p = .003).34 No between-­group differences were found
between any of the stimulation techniques or for any of the studied
34
variables.
4  |   D I S C U S S I O N
Through a literature search of non-­pharmacological therapies for
pain management in PD, 12 studies were included in the analysis
based on the inclusion criteria. These studies spanned five primary
techniques along with one alternative measure.
4.1  |  Therapies
4.1.1  |  Exercise
Using exercise as pain management was found to be a very popular
recommendation. It was found to improve fitness, motor function,
and corticomotor functioning.30 Response times were improved im-
mediately following the exercise. Also, 79% of the participants re-
ported positive feedback following the intervention, while 21% of
the participants reported barriers and difficulties.30 Furthermore, a
case report of an 85-­year-­old PD patient showed a significant re-
duction in back pain following 5 weeks of exercise therapy. 29 One
article assessed power yoga using Vinyasa style, which significantly
decreased upper and lower limb bradykinesia score and had a large
effect size (upper limb: g  =  −1.75; lower limb: g  =  −1.11, p  <  .001).
Rigidity was also reduced, muscle strength was increased, and par-
ticipants had an improved self-­reported quality of life. This pro-
gram was also well-­tolerated by the patients and saw a high level of
adherence.31
4.1.2  |  Hydrotherapy and aquatic physical therapy
When examining hydrotherapy, a form of aquatic exercise known as
Ai Chi was researched; this exercise involved the upper and lower
limbs' combined movement in a slow coordinated rhythm.32 Ai Chi
technique was found to decrease dystonia and dyskinesia, as well
as improve postural deformities. Pérez de la Cruz32 also found a
significant difference in pain perception post-­treatment between
the experimental and control groups. A separate study found that
water-­based physiotherapy significantly reduced cervical flexion
and dorsiflexion, though dry land-­based physiotherapy did not.
Thus, a significant improvement in symmetry was noted only in the
water-­based group.32
4.1.3  |  Massage
Massage is a widespread adjunctive therapy used by PD patients
for pain. 23 When studying Thai massage therapy, a significant im-
provement in the VAS score was found in the intervention group. 25
Another technique known as Anma massage was found to reduce
muscle stiffness, difficulty in movement, and shoulder pain after a
single 40-­min session. 24
4.1.4  |  Acupuncture
Acupuncture was found to be one of the more commonly used
alternative therapies by PD patients. 26 Electroacupuncture was
found to reduce pain in PD patients but not to achieve a statis-
tically significant difference. However, it was found to signifi-
cantly reduce rigidity by 48%. Hence, electroacupuncture may
QURESHI et al.
potentially relieve pain associated with rigidity in PD patients. 28
Furthermore, in a case of a woman diagnosed with PD, having se-
vere leg pain and undergoing classical acupuncture and electroa-
cupuncture five times a week for 2 weeks, there was a reduction
in VAS score in both her right leg (70 to 16 mm) and left leg (45 to
27
5 mm).
4.1.5  |  Neuromodulation
Several methods of neuromodulation were observed in this review.
For DBS, a significant decrease in pain symptoms was found at
12 months after unilateral (p = .0009) and bilateral (p = .014) inter-
vention, hence supporting the use of STN DBS in managing long-­
term pain.38 In addition, support was shown for the benefit of STN
DBS as an acute pain treatment method with the number of patients
reporting pain as significantly reduced at the 1-­week assessment
41
(p = .009). Central-­related pain (such as dystonic pain) was noted
as being the most responsive to DBS, with reports of 100% improve-
ment at 3 months.35 This highlights the strong impact that DBS has
on central sensory processing. On the other hand, peripheral-­related
pain (such as musculoskeletal pain) was found to be the least respon-
35
sive, with only a 14% improvement at 3 months. Hence, DBS shows
specificity in alleviating certain pain types, while not others. Due to
this high specificity, patients may consider DBS as an additive pro-
cedure for their current treatment protocol in managing pain. Next,
SCS and its effect on pain relief and motor symptoms were studied.
The results found that all patients in the study reported significant
improvement in VAS pain scores following SCS implantation, with a
mean reduction of 59% (two-­t ailed t test, p < .005).34 The study also
found that patients who received cycling burst stimulation had an
34
average of 67% reduction in VAS scores. In comparison, patients
who received the continuous burst stimulation had an average de-
34
crease of 48%. When looking at the motor symptoms, 73% of all
patients improved in the 10-­meter walk, with an average improve-
34
ment of 12% (two-­t ailed paired t test, p = .003). 64% of patients
showed a clinically significant improvement in Timed up and Go
completion time, with an average improvement of 21% (two-­t ailed
34
paired t test, p = .003).
Although studies on transcranial direct current stimulation
(tDCS) and TMS did not fulfill our inclusion criteria, it is a prominent
neuromodulation technique in PD, and hence, it is important to ap-
praise the research surrounding tDCS or TMS and pain.
Transcranial direct current stimulation (tDCS) is a form of non-­
invasive brain stimulation that sends low-­amplitude electrical cur-
rent to the cortex using scalp electrodes, with the aim of modulating
cortical excitability.17 Studies have used tDCS to modulate NP, which
is pain caused by disease or lesions in the somatosensory nervous
system, the primary motor area (M1), and dorsolateral prefrontal
cortex (DLPFC). A systematic review examined eight articles observ-
ing different causes for NP, including spinal cord injury (SCI), am-
putation, stroke, multiple sclerosis (MS), and radiculopathy.17 tDCS
was applied to M1, DLOFC, and the posterior parietal cortex.17 A
|
      13
considerable reduction in NP was observed in all studies when using
tDCS, except for one with SCI and another one with radiculopathy.17
The selected articles showed good evidence for internal validity with
an average of 8.5 points (95% CI, 7.5–­9 points) on the PEDro scale.17
Another study focused on tDCS and its effectiveness in improving
motor and non-­motor symptoms in people with idiopathic PD. The
researchers focused on six trials that measured different symptoms,
with the first one being impairment.63 Using the Unified Parkinson's
Disease Rating Scale, no evidence of effect was found (mean dif-
ference [MD]: −7.10, 95% confidence interval [CI]: −19.18 to 4.97).63
Next, gait speed was measured and there was no evidence of an ef-
fect found (standardized mean difference [SMD]: 0.50, 95% CI: −0.17
to 1.18).63 They also looked at the reduction in OFF time and ON
time in patients with dyskinesia and found no evidence of an effect
(MD: 0.10 h, 95% CI: −0.14 to 0.34; and MD: 0.00 h, 95% CI: −0.12 to
0.12; I2 = 0%).63 Overall, there was very low-­quality evidence for all
the trials, and hence, the effectiveness of tDCS in improving motor
and non-­motor symptoms could not be substantiated.63
Transcranial magnetic stimulation (TMS) is another technique
of non-­invasive brain stimulation. TMS involves generating a
brief, high-­intensity magnetic field that can excite or inhibit parts
of the brain. 64 Most studies focus on the motor cortex where a
focal muscle twitch, called the motor-­evoked potential, can be
produced. 64 This can be used to map brain function and excitabil-
ity of different regions. 64 TMS has clinical use as it can stimulate
the motor cortex in a similar way to epidural stimulation and can
reduce NP in some groups of patients. 64 A study was conducted
that focused on delivering repetitive TMS over the motor cortex's
hand area for 5 consecutive days.18 Pain was assessed using the
VAS and the Leeds assessment of neuropathic symptoms and signs
(LANSS) scale.18 The results showed that both groups of patients
(one group with trigeminal neuralgia [TGN] and the other with
post-­s troke pain syndrome [PSP]) displayed a significant decrease
(p < .05) in pain ratings with a mean reduction of 45% at the end
of the fifth treatment, and 40% 2 weeks later.18 It is important to
note that PSP and TGN groups were initially separated for analy-
sis, but later combined as there were no apparent differences be-
tween these two groups.18
4.2  |  Alternative therapies
Another technique that is known to reduce the perception of pain
is music therapy. While there is considerable evidence for music in
pain reduction, literature regarding music alleviating pain specifically
in PD patients is scarce. Nevertheless, music as a treatment for pain
in PD is supported by its ability to reduce pain commonly found in
PD.65,66 However, because all the studies found using music therapy
did not meet the inclusion criteria, it was not part of the major cat-
egories of non-­pharmacological therapies.
Music's effects alone, and in combination with other pain man-
agement programs, have been found to be helpful in pain reduc-
tion. 67 Music therapies will often contain specific elements meant
 |
14      QURESHI et al.
to improve the listener's positivity and mood. 68 Thus, the music
used in therapy may be different than music used for recreational
purposes, and hence, patients must be selective in their choice
of music. Music therapy was found to reduce the perception of
thermal pain. 68 Furthermore, it reduced anxiety and the use of
analgesics in post-­operative patients. 69,70 Harp music was found
to significantly correlate with decreased fatigue and pain in hos-
pital patients.71 Along with reductions in joint pain57 and back
pain, 58 music has also been found to release endogenous opioids,
67
oxytocin, and other amines that are involved in reducing pain.
Furthermore, an alternative type of music therapy known as vi-
broacoustic therapy has been shown to reduce rigidity, which is a
significant cause of pain for PD patients.72
4.3  |  Future directions
In future studies, there are several improvements or changes that
could be made in order to better study non-­pharmacological meth-
ods of dealing with pain in PD patients. Exercise was found to be a
solid adjunction for pain reduction, but it may not be therapeutic in
attenuating fatigue. In essence, as exercise is already incorporated
in many treatment regimens in PD, it may be helpful to investigate
which specific forms of exercise are most beneficial for reducing
Parkinson-­related pain such that it may be incorporated into pain
management as well. For hydrotherapy, future research warrants
large RCTs in order to gain more insight into the mechanisms of pos-
32
tural deformities. This would also help to determine the expected
time needed to achieve a meaningful improvement. Currently, pro-
viding evidence for how Anma massage therapy affects the central
nervous system is very difficult to obtain. Further studies examin-
ing Anma massage therapy should focus on how this therapy alters
24
the central nervous system to help reduce pain in PD. For Thai
massage therapy, further studies during the “off” and “on” states
are needed to determine its efficacy in the management of pain. 25
As acupuncture may be useful for pain management in PD patients,
further investigation of variables, including the number of sessions
and the length of each session, should be studied for more accu-
rate inclusion into pain management protocols. Studies should also
examine different acupuncture approaches, such as using alternate
acupuncture points. 26 To improve upon tDCS in treating pain in idi-
opathic PD, large, multicentered RCTs with a parallel-­group design
and broad inclusion criteria are needed to not only strengthen the
evidence base but also inform clinical guidelines for systematic
stimulation protocols63 Also, for tDCS, the methodological qual-
ity of future studies with regard to blinding of personnel, relation
to allocation concealment, and intention-­to-­treat analysis needs to
be improved along with dropout and adverse event reporting.63
Next, due to DBS specificity, this procedure has a positive impact
36,41
on affective states, particularly emotionality. Therefore, further
research is warranted to understand the specific nature of the ef-
fective improvement among such patients, as the evidence seems to
show that DBS may have an effect in improving emotionality.41,42 In
terms of SCS, future studies should be conducted that analyze the
use of SCS as a salvage therapy for PD symptoms following failed
DBS therapy.34
4.3.1  |  Limitations
Despite the results found from these studies, there are certain limi-
tations to take note of. In exercise therapy, the interpretation of the
magnitude of effect size may have been influenced by the small
sample size.31 Also, assessors were unblinded and hence may have
influenced the results. Furthermore, patients were observed in an
uncontrolled environment and the presence of numerous external
factors could have affected the patient's progression or regression. 29
In hydrotherapy, there was a reduced sample size, which may have
led to an exaggeration of the magnitude of effects reported, and
also, there was a relatively short follow-­up.33 For massage therapy,
the study was conducted in one medical facility in a small local city;
hence, the results are not likely generalizable to other settings. 23,24
In the Thai massage study, not only were sessions solely conducted
during the “on” periods, but there was a lack of objective evaluations
of pain during follow-­up visits. This led to a limited understanding of
the duration of the effect of Thai massage. 25 One limitation of acu-
puncture therapy was that the small number of participants caused
the results to be considered preliminary. 28 The treatment was also
observed over 3 weeks, which precludes investigation of the poten-
tial beneficial effects from a longer duration of treatment. 28 There
were several limitations to the SCS study. For one, not every patient
was able to complete the TUG and the 10-­meter walk, resulting in
a decreased sample size for these two tests.34 Also, the spinal cord
stimulator was not placed in the same spinal location for all patients
due to differences in presenting pain symptoms.34 Furthermore, in
the tDCS study, due to the shortage of useful quality articles, the
varying ramp-­on and ramp-­off durations, and the diversity of results
found, no definite conclusions could be made on the efficacy of neu-
romodulating effects of tDCS on NP.17
5  |  CO N C LU S I O N
Pain management in PD is often a complicated task. Since there
are many dilemmas in its management, more non-­traditional tech-
niques known to relieve pain should be investigated for their overall
efficacy and potential benefits. Exercise, massage, hydrotherapy,
acupuncture, and neuromodulation are some of the more common
methods used to reduce pain. While there are numerous sources
of support for these procedures in reducing pain, investigation of
their effects on PD patients is limited. However, since the literature
provides ample support for their potential in relieving pain in PD
patients, further research through methodologically robust studies
should be conducted. With further exploration, specific alternate
procedures catered to PD patients may prove beneficial in the man-
agement of pain.
QURESHI et al.
AC K N OW L E D G M E N T
All authors have no acknowledgments to declare.
C O N FL I C T O F I N T E R E S T
The authors declare that the research was conducted in the absence
of any commercial or financial relationships that could be construed
as a potential conflict of interest.
AU T H O R C O N T R I B U T I O N S
Abdul Rehman Qureshi, Eraad Rahman, Dion Paul, Yazan Shamli
Oghli, Mohammed Mulaffer, Danial Qureshi, and Muhammad Affan
Danish played a substantial role in contributing to the conception
and design of the work, drafting the work, and revising it critically
for important intellectual content, have given final approval of the
version to be published, and agreed to be accountable for all as-
pects of the work in ensuring that questions related to the accu-
racy or integrity of the work are investigated and resolved. Abdul
Qayyum Rana conceived the study, analyzed the data, interpreted
the work, drafted the work, revised it critically for important intel-
lectual content, and has given final approval of the version to be
published. Muhammad Khizar Jamal has also agreed to be account-
able for all aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are appropri-
ately investigated and resolved. Muhammad Khizar Jamal analyzed
and interpreted the work, drafted the work, revised it critically for
important intellectual content, and has given final approval of the
version to be published. Muhammad Khizar Jamal has also agreed
to be accountable for all aspects of the work in ensuring that ques-
tions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.
DATA AVA I L A B I L I T Y S TAT E M E N T
Not applicable.
ORCID
Muhammad Khizar Jamal  https://orcid.
org/0000-0002-4992-6950
REFERENCES
1. Munazza S, Ford B. Management of pain in Parkinson's disease.
CNS Drugs. 2012;26(11):937-­948.
2. Skogar O, Lökk J. Pain management in patients with Parkinson's
disease: challenges and solutions. J Multidiscip Healthc.
2016;9:469-­479.
3. Bonnet AM, Jutras MF, Czernecki V, Corvol JC, Vidailhet M.
Nonmotor symptoms in Parkinson's disease in 2012: relevant clini-
cal aspects. Parkinson's Dis. 2012;2012:198316.
4. Beiske A, Loge J, Rønningen A, Svensson E. Pain in Parkinson's dis-
ease: prevalence and characteristics. Pain. 2009;141(1):173-­177.
5. O'Sullivan SS, Williams DR, Gallagher DA, Massey LA, Silveira-­
Moriyama L, Lees AJ. Nonmotor symptoms as presenting com-
plaints in Parkinson's disease: a clinicopathological study. Mov
Disord. 2008;23:101-­106.
6. Rana A, Qureshi ARM, Rahman N, Mohammed A, Sarfraz Z, Rana
R. Disability from pain directly correlated with depression in
Parkinson's disease. Clin Neurol Neurosurg. 2017;160:1-­4.
|
      15
7. Roh JH, Kim BJ, Jang JH, et al. The relationship of pain and health-­
related quality of life in Korean patients with Parkinson's disease.
Acta Neurol Scand. 2009;119(6):397-­4 03.
8. Tinazzi M, Vesco C, Fincati E, et al. Pain and motor compli-
cations in Parkinson's disease. J Neurol Neurosurg Psychiatry.
2006;77(7):822-­825.
9. Mylius V, Brebbermann J, Dohmann H, Engau I, Oertel WH, Möller
JC. Pain sensitivity and clinical progression in Parkinson's disease.
Mov Disorde. 2012;26(12):2220-­2225.
10. Busse JW, Bartlett SJ, Dougados M, et al. Optimal strategies
for reporting pain in clinical trials and systematic reviews: rec-
ommendations from an OMERACT 12 workshop. J Rheumatol.
2015;42(10):1962-­1970.
11. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological qual-
ity and synthesis of case series and case reports. BMJ Evid Based
Med. 2018;23(2):60-­63.
12. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-­I: a tool for as-
sessing risk of bias in non-­randomised studies of interventions.
BMJ. 2016;355:i4919.
13. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane
Collaboration's tool for assessing risk of bias in randomised trials.
BMJ. 2011;343:d5928.
14. Hernandez-­reif M, Field T, Krasnegor J, Theakston H. Lower back
pain is reduced and range of motion increased after massage ther-
apy. Int J Neurosci. 2001;106(3-­4):131-­145.
15. Adams R, White B, Beckett C. The effects of massage therapy
on pain management in the acute care setting. Int J Ther Massage
Bodywork. 2010;3(1):4-­11.
16. Romanowski M, Romanowska J, Grześkowiak M. A compar-
ison of the effects of deep tissue massage and therapeutic
massage on chronic low back pain. Stud Health Technol Inform.
2012;176:411-­414.
17. David MCMM, Moraes AA, Costa MLD, Franco CIF. Transcranial
direct current stimulation in the modulation of neuropathic pain: a
systematic review. Neurol Res. 2018;40(7):555-­563.
18. Khedr EM, Kotb H, Kamel NF, Ahmed MA, Sadek R, Rothwell JC.
Longlasting antalgic effects of daily sessions of repetitive tran-
scranial magnetic stimulation in central and peripheral neuropathic
pain. J Neurol Neurosurg Psychiatry. 2005;76(6):833-­838.
19. Buhmann C, Wrobel N, Grashorn W, et al. Pain in Parkinson dis-
ease: a cross-­sectional survey of its prevalence, specifics, and ther-
apy. J Neurol. 2017;264(4):758-­769.
20. Suoh S, Donoyama N, Ohkoshi N. Anma massage (Japanese mas-
sage) therapy for patients with Parkinson's disease in geriatric
health services facilities: effectiveness on limited range of motion
of the shoulder joint. J Bodyw Mov Ther. 2016;20(2):364-­372.
21. Casciaro Y. Massage therapy treatment and outcomes for a pa-
tient with Parkinson's disease: a case report. Int J Ther Massage
Bodywork. 2016;9(1):11-­18.
22. Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current
stimulation (tDCS) for idiopathic Parkinson's disease. Cochrane
Database Syst Rev. 2016;7(7):CD010916.
23. Donoyama N, Ohkoshi N. Effects of traditional Japanese mas-
sage therapy on various symptoms in patients with Parkinson's
disease: a case-­s eries study. J Altern Complement Med.
2012;18(3):294-­299.
24. Donoyama N, Suoh S, Ohkoshi N. Effectiveness of Anma mas-
sage therapy in alleviating physical symptoms in outpatients with
Parkinson's disease: a before-­after study. Complement Ther Clin
Pract. 2014;20(4):251-­261.
25. Miyahara Y, Jitkritsadakul O, Sringean J, Aungkab N, Khongprasert
S, Bhidayasiri R. Can therapeutic Thai massage improve upper limb
muscle strength in Parkinson's disease? An objective randomized-­
controlled trial. J Tradit Complement Med. 2018;8(2):261-­266.
26. Shulman LM, Wen X, Weiner WJ, et al. Acupuncture therapy for the
symptoms of Parkinson's disease. Mov Disord. 2002;17(4):799-­8 02.
 |
16      QURESHI et al.
27. Iseki C, Furuta T, Suzuki M, et al. Acupuncture alleviated the non-
motor symptoms of Parkinson's disease including pain, depression,
and autonomic symptoms. Case Rep Neurol Med. 2014;2014:953109.
28. Toosizadeh N, Lei H, Schwenk M, 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.
29. Rosarion CL. Exercise therapy for a patient with Parkinson disease
and back pain: a case report. J Chiropr Med. 2018;17(1):72-­74.
3 0. Poliakoff E, Galpin AJ, McDonald K, et al. The effect of gym
training on multiple outcomes in Parkinson's disease: a pilot
randomised waiting-­list controlled trial. NeuroRehabilitation.
2013;32(1):125-­134.
31. Ni M, Mooney K, Signorile JF. Controlled pilot study of the ef-
fects of power yoga in Parkinson's disease. Complement Ther Med.
2016;25:126-­131.
32. Pérez de la Cruz S. Effectiveness of aquatic therapy for the con-
trol of pain and increased functionality in people with Parkinson's
disease: a randomized clinical trial. Eur J Phys Rehabil Med.
2017;53(6):825-­832.
33. Volpe D, Giantin MG, Manuela P, et al. Water-­based vs. non-­water-­
based physiotherapy for rehabilitation of postural deformities
in Parkinson's disease: a randomized controlled pilot study. Clin
Rehabil. 2017;31(8):1107-­1115.
3 4. Chakravarthy KV, Chaturvedi R, Agari T, et al. Single arm prospec-
tive multicenter case series on the use of burst stimulation to im-
prove pain and motor symptoms in Parkinson's disease. Bioelectron
Med. 2020;6:18.
35. Kim HJ, Paek SH, Kim JY, et al. Chronic subthalamic deep
brain stimulation improves pain in Parkinson disease. J Neurol.
2008;255(12):1889-­1894.
36. Pellaprat J, Ory-­Magne F, Canivet C, et al. Deep brain stimulation
of the subthalamic nucleus improves pain in Parkinson's disease.
Parkinsonism Relat Disord. 2014;20(6):662-­664.
37. Dellapina E, Ory-­Magne F, Regragui W, et al. Effect of subtha-
lamic deep brain stimulation on pain in Parkinson's disease. Pain.
2012;153(11):2267-­2273.
38. Loher TJ, Burgunder JM, Weber S, Sommerhalder R, Krauss JK.
Effect of chronic pallidal deep brain stimulation on off period dys-
tonia and sensory symptoms in advanced Parkinson's disease. J
Neurol Neurosurg Psychiatry. 2002;73(4):395-­399.
39. Jung YJ, Kim HJ, Jeon BS, Park H, Lee WW, Paek SH. An 8-­year fol-
low-­up on the effect of subthalamic nucleus deep brain stimulation
on pain in Parkinson disease. JAMA Neurol. 2015;72(5):504-­510.
4 0. Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. The benefit of subtha-
lamic deep brain stimulation for pain in Parkinson disease: a 2-­year
follow-­up study. Neurosurgery. 2012;70(1):18-­23; discussion 23-­24.
41. Marques A, Chassin O, Morand D, et al. Central pain modulation
after subthalamic nucleus stimulation: a crossover randomized trial.
Neurology. 2013;81(7):633-­6 40.
42. Cury RG, Galhardoni R, Fonoff ET, et al. Effects of deep brain stim-
ulation on pain and other nonmotor symptoms in Parkinson dis-
ease. Neurology. 2014;83(16):1403-­1409.
43. Allen N, Moloney N, van Vliet V, Canning CG. The rationale for exer-
cise in the management of pain in Parkinson's disease. J Parkinsons
Dis. 2015;5(2):229-­239.
4 4. Barceló A, Filippini B, Pazo JH. The striatum and pain modulation.
Cell Mol Neurobiol. 2012;32(1):1-­12.
45. Stagg NJ, Mata HP, Ibrahim MM, et al. Regular exercise re-
verses sensory hypersensitivity in a rat neuropathic pain model.
Anesthesiology. 2011;114(4):940-­948.
46. Rabelo PCR, Cordeiro LMS, Aquino NSS, et al. Rats with higher in-
trinsic exercise capacities exhibit greater preoptic dopamine levels
and greater mechanical and thermoregulatory efficiencies while
running. J Appl Physiol. 2019;126(2):393-­4 02.
47. Robison LS, Swenson S, Hamilton J, Thanos PK. Exercise reduces
dopamine D1R and increases D2R in rats: implications for addic-
tion. Med Sci Sports Exerc. 2018;50(8):1596-­1602.
48. Santos CR, Ruggeri A, Ceroni A, Michelini LC. Exercise training ab-
rogates age-­dependent loss of hypothalamic oxytocinergic circuitry
and maintains high parasympathetic activity. J Neuroendocrinol.
2018;30(8):e12601.
49. Ende H, Soens M, Nandi M, Strichartz G, Schreiber K. Association
of interindividual variation in plasma oxytocin with postcesarean
incisional pain. Anesth Analg. 2019;129(4):e118-­e121.
50. Janes K, Esposito E, Doyle T, et al. A3 adenosine receptor agonist
prevents the development of paclitaxel-­induced neuropathic pain
by modulating spinal glial-­restricted redox-­dependent signaling
pathways. Pain. 2014;155(12):2560-­2567.
51. Little JW, Ford A, Symons-­Liguori AM, et al. Endogenous adenosine
A3 receptor activation selectively alleviates persistent pain states.
Brain. 2015;138(1):28-­35.
52. Lena F, Iezzi E, Etoom M, et al. Effects of postural exercises in pa-
tients with Parkinson's disease and Pisa syndrome: a pilot study.
NeuroRehabilitation. 2017;41(2):423-­428.
53. Reuter I, Mehnert S, Leone P, Kaps M, Oechsner M, Engelhardt
M. Effects of a flexibility and relaxation programme, walk-
ing, and nordic walking on Parkinson's disease. J Aging Res.
2011;2011:232473.
54. Rodrigues de Paula F, Teixeira-­Salmela LF, de Morais C, Faria CD,
Rocha de Brito P, Cardoso F. Impact of an exercise program on
physical, emotional, and social aspects of quality of life of individu-
als with Parkinson's disease. Mov Disord. 2006;21(8):1073-­1077.
55. Elbers RG, Verhoef J, van Wegen EE, Berendse HW, Kwakkel G.
Interventions for fatigue in Parkinson's disease. Cochrane Database
Syst Rev. 2015;(10):CD010925.
56. Canning CG, Allen NE, Dean CM, Goh L, Fung VS. Home-­based
treadmill training for individuals with Parkinson's disease: a ran-
domized controlled pilot trial. Clin Rehabil. 2012;26(9):817-­826.
57. Winward C, Sackley C, Meek C, et al. Weekly exercise does
not improve fatigue levels in Parkinson's disease. Mov Disord.
2012;27(1):143-­146.
58. Pérez-­de la Cruz S, García Luengo A, Lambeck J. Effects of an Ai Chi
fall prevention programme for patients with Parkinson's disease.
Neurología. 2016;31(3):176-­182.
59. Kim SR, Lee TY, Kim MS, Lee MC, Chung SJ. Use of complementary
and alternative medicine by Korean patients with Parkinson's dis-
ease. Clin Neurol Neurosurg. 2009;111(2):156-­160.
60. Abe Y, Miyashita M, Ito N, et al. Attitude of outpatients with neu-
romuscular diseases in Japan to pain and use of analgesics. J Neurol
Sci. 2008;267(1-­2):22-­27.
61. Skogar Ö, Borg A, Larsson B, 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):141-­152.
62. Lim TK, Ma Y, Berger F, Litscher G. Acupuncture and neural mech-
anism in the management of low back pain-­an update. Medicines.
2018;5(3):63.
63. Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current
stimulation (tDCS) for idiopathic Parkinson's disease. Cochrane
Database Syst Rev. 2016;7(7):CD010916.
6 4. Hallett M. Transcranial magnetic stimulation: a primer.
Neuron. 2007;55(2):187-­199. https://doi.org/10.1016/j.
neuron.2007.06.026
65. Scholz D, Rohde S, Nikmaram N, et al. Sonification of arm move-
ments in stroke rehabilitation –­ a novel approach in neurologic
music therapy. Front Neurol. 2016;7:106.
66. Akmeşe ZB, Oran NT. Effects of progressive muscle relaxation ex-
ercises accompanied by music on low back pain and quality of life
during pregnancy. J Midwifery Women's Health. 2014;59(5):503-­509.
QURESHI et al. |
      17

67. Bernatzky G, Presch M, Anderson M, Panksepp J. Emotional foun- 72. Clements-­Cortès A, Vuong V. The potential of music for persons with
dations of music as a non-­pharmacological pain management tool in Parkinson's disease. Canadian Music Educator. 2016;57(3):34-­37.
modern medicine. Neurosci Biobehav Rev. 2011;35(9):1989-­1999.
68. Roy M, Peretz I, Rainville P. Emotional valence contributes to music-­
induced analgesia. Pain. 2008;134(1-­2):140-­147.
How to cite this article: Qureshi AR, Jamal MK, Rahman E, et
69. Hole J, Hirsch M, Ball E, Meads C. Music as an aid for postoperative
al. Non-­pharmacological therapies for pain management in
recovery in adults: a systematic review and meta-­analysis. Lancet.
2015;386(10004):1659-­1671. Parkinson's disease: A systematic review. Acta Neurol Scand.
70. Sihvonen AJ, Särkämö T, Leo V, Tervaniemi M, Altenmüller E, Soinila 2021;00:1–17. https://doi.org/10.1111/ane.13435
S. Music-­based interventions in neurological rehabilitation. Lancet
Neurol. 2017;16(8):648-­660.
71. Schneider D, Graham K, Croghan K, et al. Application of therapeu-
tic harp sounds for quality of life among hospitalized patients. J Pain
Symptom Manage. 2015;49(5):836-­8 45.

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