Parkinsonism and Related Disorders 19 (2013) 285e294

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Editor’s comment: Non motor symptoms are increasingly recognized to be of clinical importance for Parkinson’s disease (PD). Pain is
a universal symptom associated with almost every medical condition. Pain in PD is complex as the symptom can be multifactorial in origin.
In this article, Fil and colleagues conducted a detailed literature review of published literature on the possible mechanisms, classifications,
evaluation and potential risk factors of pain in PD. In the review, the authors highlight the limitations of published studies and the diffi-
culties in drawing guidelines and conclusions as there are significant methodological differences among published studies. This important
review draws our attention to the need for a concerted effort to conduct a multicenter evaluation with similar standardized protocols so
that possible mechanisms for pain in PD could be better understood, and risk factors could be identified early to enable more optimized
management of this disabling problem.
Eng-King Tan, Associate Editor, Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Outram road,
Singapore
Review

Pain in Parkinson disease: A review of the literature

[Universally Available]
Ayla Fil a, Roberto Cano-de-la-Cuerda b, Elena Muñoz-Hellín b, Lidia Vela c, María Ramiro-González d,
César Fernández-de-las-Peñas b, *
a
Neurologic Rehabilitation Unit, Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Hacettepe University, Ankara, Turkey
b
Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
c
Department of Neurology, Division of Movements Disorders, Hospital Universitario Fundación Alcorcón (HUFA), Alcorcón, Madrid, Spain
d
Emergency Department, Hospital de Madrid, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Parkinson’s disease (PD) is a degenerative neurological disease presenting with motor and non-motor
Received 1 August 2012 signs and symptoms. Approximately 30e50% of the patients experience pain. There is no consensus
Received in revised form regarding the mechanisms and classification of pain in PD. This paper reviews current data on the
7 November 2012
possible mechanisms, classifications, evaluation and potential risk factors for pain in PD. Literature
Accepted 22 November 2012
searches were performed to identify clinical trials and reviews covering patho-physiology, classification,
type, evaluation and risk factors associated with pain in PD. Pain in PD could be related to pathologic
Keywords:
changes in the anatomic structures involved in nociceptive mechanisms. Studies on pain mechanisms
Classification
Evaluation
have been mostly conducted in animals. The mechanism of pain is complicated and influenced by
Pain different factors. There are several methodological differences between the studies trying to classify pain
Parkinson’s disease and to characterize its subtypes. Potential risk factors for pain in PD include: age, gender, and duration of
Risk factors the disease. Although pain is one of the non-motor symptoms most frequency experienced by patients, it
Review is often under recognized and inadequately treated in contrast to motor symptoms Multicenter studies
are needed that include a large cohort of subjects evaluated in multiple dimensions including pain in
order to obtain more data and to allow improved management of pain in patients with PD.
Ó 2012 Elsevier Ltd. Open access under CC BY-NC-ND license.

1. Introduction pathways [1]. Its prevalence in the general population is 0.1e0.3%

[2], showing an increase in individuals aged
65 years [3].
Parkinson’s disease (PD) is a chronic, progressive neurodegen- Cardinal findings in PD are tremor, rigidity, akinesia (i.e., bradyki-
erative disease characterized by loss of nigrostriatal dopaminergic nesia, hypokinesia) and postural instability. In addition to motor

* Corresponding author. Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avenida de Atenas s/n, 28922 Alcorcón, Madrid, Spain. Tel.: þ34 91 488 88 84;
fax: þ34 91 488 89 57.
E-mail addresses: cesarfdlp@yahoo.es, cesar.fernandez@urjc.es (C. Fernández-de-las-Peñas).

1353-8020 Ó 2012 Elsevier Ltd. Open access under CC BY-NC-ND license.

http://dx.doi.org/10.1016/j.parkreldis.2012.11.009
286 A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294
disturbances, non-motor signs and symptoms are also common in
these patients. These symptoms are classified as autonomic, i.e.,
hyperhidrosis, orthostatic hypotension, sexual-urinary dysfunction,
thermoregulation changes, cardiovascular disturbances, peripheral
edema, dilated pupillae), sleep disturbances, neuropsychiatric
problems, i.e., apathy, fatigue, anhedonia, depression, anxiety,
panic attacks, dementia, psychosis, and sensory, i.e., internal
tremor, restless leg syndrome, numbness, paresthesia, visual
disturbances, and pain [4e7]. Among these sensory symptoms,
pain is observed in approximately 30e50% of PD patients; however,
the incidence can increase to 68e85% when all types of pain are
taken into account [8]. Pain can appear at any time during the
disease, and can be present before diagnosis [9]. There is no
consensus on the classification and the mechanisms of pain in PD
patients. The objective of this review is to review the available data
on the possible mechanisms, classification, evaluation and poten-
tial risk factors for pain in individuals with PD.
2. Methods
2.1. Data sources
We performed computerized English language literature searches to identify
clinical and controlled trials and reviews of pain in patients with PD making use of
the following databases: PubMed (from 1975), Ovid MEDLINE (from 1975), Ovid
EMBASE (from 1975), Cochrane Database of Systematic Reviews (CDSR), Cochrane
Collaboration Trials Register (CCTR), Cumulative Index to Nursing and Allied Health
Literature (CINAHL) and PEDro (Physiotherapy Evidence Database).
We used the following Medical Subject Headings (MeSH) and main key words
for searches: classification, patho-physiology, assessment, risk factors, Parkinson
disease or pain. The search was supervised by a librarian scientist who helped us
during each stage of the search. When database facilities allowed search limits,
searches were restricted to clinical or controlled trials. We also reviewed the
reference lists of the papers that we identified during the searches. Two authors
independently reviewed the selected articles. Published proceedings and abstracts
were excluded.
2.2. Data-extraction
As with article selection, data from each study were extracted independently by
2 authors. A standardized data-extraction form containing questions on population,
methodology, results, and outcome measures was used according to the Consoli-
dated Standards of Reporting Trials (CONSORT) statement. For each selected article,
the following data were recorded: inclusioneexclusion criteria, design, description
of study subject attrition and subject/investigator blinding, outcome measures, and
results. Finally, both authors had to achieve a consensus on each item on the data-
extraction form. In case of no consensus, a third author helps in the decision.
3. Results
3.1. Patho-physiology of pain and Parkinson’s disease
In 1986, pain was defined as a sensory and emotional experience
associated with real or potential injuries or described in terms of
such injuries, by the International Association for the Study of Pain
(IASP) [10]. It is known that several anatomic structures are
involved at the same time in nociception. The process leading to
pain starts with the stimulation of nociceptors. The thinly myelin-
ated Ad nociceptors response to mechanical and thermal stimuli,
while the un-myelinated C-fiber nociceptors (polymodal) usually
respond to mechanical, thermal, or chemical stimulation. The
stimuli from nociceptors arrive to the dorsal horn neurons of the
spinal cord. The lamina II, also known as substantia gelatinosa, plays
a major role in pain modulation at the spinal cord [10,11]. This area
forms an intermediate system regulating the transmission to the t-
cells on the lamina V, which in turn mediates the transmission of
sensory stimuli to the brain. The substantia gelatinosa system acts as
an inhibitory mechanism on the t-cells. Stimulation of the Ad and C
fibers inhibits the substantia gelatinosa cells, reducing the output
and their inhibitory action on the t-cells. As a result, the t-cells
increase their activity. The result is a reduction in the capacity of t-
cells to receive the stimuli or react to them. This is, essentially, the
gate-theory mechanism at the spinal level [12].
Two phylogenetically distinct systems, the medial and lateral
pain systems, transmit pain to higher center brain neurons. The
medial system is mainly constituted of paleospinothalamic, spi-
nomesencephalic, spinoreticular, spinoparabrachial hypothalamic
and spinothalamic tract fibers. These fibers travel in a caudal and
rostral direction to higher centers by terminating in the para-
brachial nucleus, the locus cæruleus (reticular formation), the peri-
aqueductal gray substance (mesencephalon), intra-laminar and
medial thalamic nuclei, thalamic ventral caudal parvocellular
nucleus and ventral caudal portae, the insula, parietal operculum,
the secondary somatosensory cortex, the amygdale and hippo-
campus (Fig. 1). The medial system is involved in the affective and
cognitive-evaluative dimension of pain, pain memory, and auto-
nomic responses. Similarly, the lateral system is formed by the
neospinothalamic, the neotrigeminothalamic, and the cervical
bundle and the beam of the dorsal horn. In the higher centers, these
fibers terminate in the lateral thalamus, the primary and secondary
somatosensory areas, the parietal operculum and the insula (Fig. 1).
The lateral system is important for the sensory-discriminative
component of pain since it provides information about pain local-
ization and duration [10,11,13,14].
The descending pathways originating in the brain stem and
cerebral structures also play an important role in the integration
and modulation of nociceptive information in the dorsal horn. The
serotonergic, noradrenergic and dopaminergic networks are the
principal components of these descending pain mechanisms. The
sensitivity of the dorsal horn neurons can be increased or decreased
by these pathways [11].
PD, as a multifocal degenerative and progressive disease, could
affect the pain process at multiple levels, from the transmission of
the pain from peripheral structures to the higher centers, to its
reception and interpretation as well as interfering with several
anatomic structures involved in pain mechanism. In a study with
PD patients, Nolano et al. showed that significant losses occur at the
level of free nerve endings and encapsulated nerve endings (i.e.,
Meissner’s corpuscles), independently of age or disease duration
[15]. They indicated that these changes in receptor size and
peripheral deafferentation could play a relevant role in the patho-
genesis of the sensory dysfunction of PD [15]. Starting in early stage
PD, degenerative changes can also occur in the spinal cord. Certain
neuronal losses have been observed in Lamina I of the posterior
spinal horn [16].
Braak et al. divided the disease into 6 periods [17,18]. The
changes typical of the pre-motor period start in the olfactory bulb
and progress toward the inferior brain stem area (including the
medulla oblongata and pontine tegmentum) of Lewy neurites and
Lewy bodies (period 1e2). In the following symptomatic periods,
pathologic changes take place in the mid brain including the sub-
stantia nigra (period 3), the meso-cortex (period 4), and finally the
neo-cortex (periods 5e6) [17,18]. Nociceptive information cannot
be transmitted directly from the spinal cord to higher centers
[19,20], since it is modulated by the descending pathways involving
various brain stem nuclei. Some of these nuclei are affected early in
PD [21]. As a result, this classification into 6 periods can be helpful
for understanding those changes taking place in the anatomical
structures of the pain related higher centers during the course
of PD.
When examining the brain stem in PD, it is observed that ros-
tromedial medulla, comprising the nucleus raphe magnus and
gigantocellular reticular nucleus, starts to be affected in period 2 of
PD. This area is important for its role in the descending regulation
of pain since it is the last station of the descending anti-nociceptive
 A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294 287

Fig. 1. Central pain pathways in Parkinson’s disease. Left: The lateral system is formed by the neospinothalamic, the neotrigeminothalamic, the cervical bundle and the beam of the
dorsal horn which fibers terminate in the lateral thalamus, the primary and secondary somatosensory areas, the parietal operculum and the insula. Right: The medial system is
mainly constituted by the paleospinothalamic, spinomesencephalic, spinoreticular, spinoparabrachial hypothalamic and spinothalamic tract fibers which terminate in the para-
brachial nucleus, the locus cæruleus, the peri-aqueductal gray substance, intra-laminar and medial thalamic nuclei, thalamic ventral caudal parvocellular nucleus and ventral caudal
portae, the insula, parietal operculum, the secondary somatosensory cortex, the amygdale and hippocampus.

pathways [22,23]. The locus coeruleus plays a role in the nocicep-
tive modulation within the thalamus [24]. Consequently, the
presence of Lewy bodies in the coeruleus/sub-coeruleus area,
which also plays a role in the noradrenergic modulation of pain, as
well as in intra-laminar and medial thalamic nuclei, could have an
effect on autonomous, motivational-emotional and cognitive-
evaluative responses [13e25]. Serotonergic input to the spinal
dorsal horn from the caudal raphe affects the mechanisms of pain
by facilitating the nociceptive transmission of the mechanical
stimuli, and through such facilitation repressing the first reaction to
neurologic inflammation and to the chemical activation of primary
afferents [26]. The caudal raphe nuclei and the nucleus raphe
magnus, which are reciprocally linked [27], together with the
coeruleus/sub-coeruleus area, make up the functional gain-setting
system. This system transforms important inputs from the higher-
level components of the limbic lobe into descending projections by
controlling the excitability of the spinal and medullary pre-motor
and motor neurons of the somato-motor system [28,29].
Together with the locus coeruleus, the gigantocellular nucleus
and the nuclei of the bulbar raphe, the peri-aqueductal gray matter
and the parabrachial nuclei play an important role in the modula-
tion of spinal nociceptive transmission, e.g., on inhibition of noci-
ceptive stimuli coming from the dorsal horn neuron. A disturbance
in this pain-inhibiting region could cause an increase in the
sensation of pain [13].
The lateral thalamus, one of the higher centers important for
pain mechanisms, also plays a major role in central pain. Dener-
vation of the nigrostriatal system increases neuronal activity in the
subthalamic nucleus, the internal globus pallidus, and the sub-
stantia nigra pars reticulata. Hyperactivity in these areas leads to
a strong inhibition of the lateral thalamic region, which can affect
pain mechanisms in two different ways: 1), disinhibition of medial
spinothalamic-cortical pathways to the anterior cingulate cortex
due to the disruption of the lateral spinothalamic-cortical pathway
to the parietoinsular system [30]; 2), inhibition of the lateral thal-
amus reducing localization, one of the sensory discrimination
elements of pain. The difficulty that patients have in localizing their
pain symptoms supports this hypothesis. On the other hand, other
properties of sensory discrimination become more sensitive to
sensory stimuli [13]. This may explain the changes in pressure and
thermal pain thresholds observed in PD.
Animal studies analyzing the effects of basal ganglia and
dopamine on sensory pathways and their contribution to sensory
perception reflect the importance of this region for pain [19].
The neurons within the substantia nigra are responsive to low-
intensity deep mechanical stimuli (e.g. brushing, tapping, pressure)
and electrical stimuli which decrease or increase the discharge ratio
as compared to resting discharge. The nigral neuron responses can
depend on behavioral situations including the application of low-
intensity stimuli. As with non-nociceptive nigral neurons, noci-
ceptive neurons within the substantia nigra may respond with
suppression or enhancement of discharge frequency following
noxious stimulation and have large receptive fields that often
include the whole body. The large receptive fields of nociceptive nigral
neurons show that these neurons have no major effect on the spatial
localization of painful stimuli [19]. Some studies, however, have
288 A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294
reported the importance of these neurons on the codification of
noxious stimuli [31], indicating that certain nociceptive nigral neurons
may play a relevant role in sensory discrimination [19]. Animal
experiments have shown that stimulating the substantia nigra leads to
nociceptive inhibition by activating the spinal cord neurons through
dopaminergic pathways [32e35]. Based on the results of these studies,
it could be postulated that involvement of the substantia nigra in
patients with PD affects the discriminatory aspect of pain and
behavioral pain responses. In addition, striatal neurons that respond to
low-threshold somatosensory stimulation also have large cutaneous
receptive fields [36] and can play a role in the localization of and the
response to stimuli from circumscribed regions [37e39].
Multi-sensory inputs within the striatum lead to the view that this
area plays a role in the coordination of behavioral responses by
integrating sensory information conveyed by different sensory
methods. The wide dynamic range of neurons, which exhibit low
mechanical thresholds, are sensitive to somatosensory stimuli across
a broad range of stimulus intensities and are maximally responsive to
noxious stimuli as well, some nociceptive neurons within the stria-
tum could be coding for the intensity of noxious stimuli. The ability of
striatal neurons to receive nociceptive stimuli from a large receptive
area might indicate that these structures do not play a role in the
spatial localization of painful stimuli; the striatum may, however, act
in concert with somatotopically organized areas that are co-activated
and provide precise spatial information for the next level of integra-
tion [19]. Dopamine secretion during painful stimuli has been iden-
tified within the dorso-lateral striatum. This type of response depends
on the subjective perception of pain intensity. Additionally, the
ventral striatum is clearly related to the emotional dimension of the
human pain process and expectation [40]. In conclusion, striatum
involvement in PD could affect the emotional dimension of pain and
the subjective perception of pain intensity.
Dopamine may also modulate pain at different levels including
the spinal cord, thalamus, peri-aqueductal gray matter, the basal
ganglia and the cingulate gyrus [41]. Axons coming from key
dopaminergic areas, such as the substantia nigra pars compacta,
the ventral tegmental area and the hypothalamus project to mes-
ocortical, mesolimbic, nigrostriatal and tuberoinfundibular path-
ways. These pathways mediate different non-motor symptoms, e.g.,
cognition, sleep and pain [41]. Mendlin observed that serotonin was
not secreted after blocking postsynaptic D2 receptors in rats [42].
Serotonin secretion in the forebrain is dependent on intact local
dopaminergic neurotransmission, as serotonin has an important
role in the sensory and emotional properties of pain. A lesion of the
striatum dopamine terminals can also modify pain transmission
[43]. A significant reduction of the nociceptive delay and an
acceleration of the initial and final periods of nociceptive stimula-
tion have been observed with lesions of this area. This condition
effectively increases the nociceptive stimuli [44]. Finally, in a posi-
tron emission tomography (PET) study conducted by Brefel-
Courbon et al. increased brain activity during “off” periods was
observed in the right insular, right prefrontal and left anterior
cingulate cortex when subjects were exposed to experimental pain
[20]. It was suggested that levodopa could reverse these results. In
several pain studies, changes in threshold were observed after the
administration of levodopa [20,45,46]. These results reveal the
importance of dopamine in pain transmission.
3.2. Classification and types of pain in Parkinson’s disease (PD)
Pain in PD manifests in different parts of the body and different
types of pain has been described. As a result, no consensus has been
reached on the classification of pain in PD. Classification generally
follows the etiology of the pain [8,47e54]. Snider et al. distin-
guished two main groups of sensory and pain symptoms: primary
(i.e. originating in the nervous system) and secondary (other
sources than the nervous system, e.g., the musculoskeletal) [47]. As
new knowledge has emerged regarding the mechanisms, frequency
and other properties of pain, more comprehensive classifications
have been proposed (Table 1). Ford’s classification is the most
commonly used [55]. Ford [55] and Goetz et al. [48] distinguish the
following categories: musculoskeletal pain, radicular/neuropathic
pain, dystonia-related pain, akathitic discomfort/pain and central
parkinsonian pain [48,55]. Finally, classifications that correlate the
pain, directly or indirectly, with the disease have recently been
proposed [48,55].
Musculoskeletal pain covers pain arising from muscular, joint
and postural etiologies, including muscle cramps. Muscle cramps or
tightness in patients with PD can affect any part of the body but it
appears more typically in the neck, arm, paraspinal or calf muscles;
while joint pain occurs most frequently in shoulder, hip, knee, and
ankle. The prevalence of musculoskeletal pain ranges from 45% to
74% in those patients with PD experiencing pain [8,47,48,51e56].
This prevalence rate is much higher than that reported in the
general population (8%e25%) [47,51,52]. The treatment of muscu-
loskeletal pain in PD can vary depending on the cause. If the pain is
due primarily to parkinsonian rigidity, dopaminergic therapy,
physical therapy, and exercises are indicated [55].
Radicular-neuropathic pain manifests itself with pain, numbness
or weakness in the area of a nerve root as a consequence of nerve or
root compression [55]. Postural abnormalities and dystonia devel-
oping during the disease can lead to this type of pain through
discopathy [57]. The prevalence of radicular-neuropathic pain in
patients with PD experiencing pain ranges from 5% to 20%
[8,48,51e54,56].
Dystonic pain is represented by dystonic spasms which are
usually paroxysmal, spontaneous, or triggered by movement or
activity. They can be observed in the extremities, the face and the
pharyngeal muscles and are considered among the most painful
symptoms that a patient with PD may experience. The prevalence
of dystonia-related pain ranges from 8% to 47% [8,48,50e52,56] in
patients with PD experiencing pain. In contrast, this pain is not
present in healthy people. Symptoms can be more intense as early
morning manifestation of dopaminergic deficiency, and their
intensity decreases after dopaminergic medication [58]. In the old
days with high dose levodopa patients had ON dystonia as well.
Central pain is an insistent pain not restricted to nerve or
radicular territories that manifest as neuropathic sensory events
such as paresthesia or shooting pain. The patient usually describes
it as a bizarre and unexplained painful sensation predominately in
the more affected side and in the “OFF” state [47,59,60]. Central
pain can occur in different areas of the body including: the mouth,
rectum, vagina, abdomen, chest and testes [61e64]. The prevalence
of central pain in patients with PD is 10%e12% [8,53]. Central pain
can be mainly modified by dopaminergic medication as it seems to
be related to an abnormal function of the medial spinor-
eticulothalamic pathways [55]. In cases refractory to standard
treatment, conventional analgesics, opiates, tricyclics may be also
helpful [55].
The term akathitic discomfort (akathisia) is used to describe
subjective restlessness or the painful impulse to move continually.
It seems clear that this pain improves with levodopa treatment
[55].
Restless leg syndrome (RLS) is another source of pain in
patients with PD. It is defined as a sensory-motor disturbance
that is prominent at night and improves with movement. It
includes intense and disagreeable sensations (paresthesia and
dysesthesia) of the extremities, more pronounced in the lower
extremities [65]. Some reports have indicated that the prevalence
of RLS in patients with PD ranges from 8% to 20% [66,67], which is
Table 1
Categorization and rate of pain in Parkinson’s disease.
Author Number subjects Pain evaluation Rate of pain Classification of pain Rate of pain types Localization Factors affecting pain
Snider et al. [47] 101 PD patients Medical record PD patients (40%) Pain related to central nervous PD patients/No PD Head or back, hand, foot Levodopa
149 No PD patients No PD (8%) system dysfunction 11/0 Restless leg syndrome
Burning 22/3
Tingling 21/1
Numbness 29/3
Pain
Goetz et al. [48] 95 PD patients McGill Questionnarie 19 female (44%) Muscular pain: muscle cramps, 32 (74%) Neck, paraspinal muscles, calf Fluctuations
(43 female, 52 male) 24 male (46%) tightness 12 (28%) muscles Levodopa
(43 pain, 52 no pain) Dystonic pain: painful dystonia 6 (14%) Feet Disability
Radicular and neuritic pain: tingling 1 (2%) All body Worsening of
Diffuse generalized pain: discomfot of 6 (14%) Shoulders, hips, knees, ankles Parkinsonian
akathisia 0 (0%) symptoms Posture
Joint pain: stiffness, pain with motion, Increased resting tone
confused with joint
Talamic pain: Constant, boring,
ineffable and poorly lokalized pain

A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294

Scott et al. [49] 943 PD patients Questionnarie: SP-1/SP-2 One or more types Pain reported by patients (there is or Female/Male Neck Gender
(356 female, 587 male) and areas of pain per not) 53.7%/44.9% Low back
patient Neck pain 48.3%/40.7% Calf muscle
Back pain 45.3%/41.4%
Muscle cramps
Giuffrida et al. [54] 388 PD patients UPDRS (motor) 269 (67%) Muscular pain: stiffness, cramps, 94% e Motor fluctuations
(202 male, 186 female) 40.6  19.6 One or more types and pseudo-cramps, pasms 51%
(269 pain, 119 no pain) 43.8  14.8 areas of pain per Osteo-ligamentar rheumatologic pain: 2%
49.4  14.9 patient articular, spinal, peri-articular
43.9  13.8 Neurogenic painful syndromes:
paresthesia, dysesthesia, burning
sensation
Tinazzi et al. [50] 117 PD patients VAS 47 (40%) Musculoskeletal pain: aching, 21% For all types of pain Motor complications
(50 male, 67 female) cramping, arthralgic, joint 8% Neck: 2.5%
(47 pain, 70 no pain) Dystonic pain: pain associated with 40% Shoulder: 4%
dystonic movements 4% Arm: 1%
Central primary pain: burning, tingling Back: 9%
formication, bizarre quality Leg or foot: 28%
Akathitic discomfort
Lee et al. [56] 123 PD patients Wisconsin Brief 85% (according to Nociceptive pain: somatic and visseral 94.7% Legs: 37.9% Not described
(64 female, 59 male) Pain Inventory, PACA) Neuropathic pain 5.3% Back: 16.5%
PACA and VAS Musculoskeletal pain 62.6% Feet: 11.2%
Dystonic pain 67% Arms: 10.5%
PD treatment-related pain 0.8% Neck: 9.1%
Other causes 4.1% Hands: 6.7%
Negre-Pages et al. [51] 450 PD patients VAS, DoPaMiP, 62% PD patients with Dystonic pain 36% Head: 8.7% Motor complications
(254 male, 196 female) McGill Pain Questionnaire, chronic pain Neuropathic pain 7% Back: 12.6% Depressive symptoms
98 control The Brief Pain Inventory 5.5% PD patients with Akathisia 5% Upper limbs: 21.4% Age
(53 male, 45 female) non-chronic pain Muscular pain: Deep aching, myalgia, 2% Lower limbs: 67% PD duration
58.2% control subject cramps, stiffness or articular discomfort 31% Head: 11% Dyskinesia
Non-PD pain Back: 61% Severity of PD
Upper limbs: 14% Levadopa
Lower limbs: 30%
Defazio et al. [52] 402 PD patients VAS PD Patients (70%) Dystonic pain 6.7% Neck or shoulder: 6.2% Depression
(148 female, 254 male) Healthy (63%) Muscular pain: cramping, spams, joint 25.4% Arm: 11% Medical conditions
317 matched controls pain, pain with motion 4.7% Back: 15.7% Age
(138 female, 179 male) Peripheral neuropathic: pain in the 4.5% Leg or foot: 19.9%
territory of a root or nerve
Central neuropathic pain: burning,
tingling, formication, or bizarre quality

289
(continued on next page)
 290 A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294

much higher than the prevalence found in the general population

PD: Parkinson’s disease; UPDRS: Unified Parkinson’s Disease Rating Scale; VAS: Visual analogue Scale; PACA: Palliative Care Assessment Tool; DoPaMiP: Douleur et maladie de Parkinson en Midi-Pyrénées; LANSS: Leeds
Factors affecting pain

(1%) [66].
In conclusion, the prevalence of all types of pain experienced
Female gender

by individuals with PD is reported to be over 80% (Table 1);

however, discrepancies can be observed among the studies due to
Akathisia

different methodologies. Since pain and sensory symptoms in PD

represent a broad spectrum, a multidisciplinary approach to pain
management is recommended. Nevertheless, it has been found
that that 50% of patients with PD-related pain did not receive
treatment [8].

3.3. Pain assessment in Parkinson’s disease (PD)

Not described

Not described
Rate of pain types Localization

Pain thresholds have been evaluated with instruments such as

the visual analog scale or the McGill Pain Questionnaire in indi-
viduals with PD. Additionally, quantitative sensory testing
including thermal, electrical and mechanical pain thresholds have
been also assessed in patients with PD [15,20,45,46,59,68e72]
(Table 2). The results revealed several discrepancies including
patient’s profile, pain threshold assessment, part of the body
44.4%
11.1%
19.1%
12.7%
12.7%

examined, outcomes included, the assessment during ONeOFF

70%
20%
40%
10%

periods, and the use of levodopa. As a result, while some studies

had reported lower pain thresholds in individuals with PD
Mixt pain: more than one of type pain
Central parkinsonian pain: burning,

[45,46,69,72]; others report no differences [59,68,73], whereas one

study revealed higher thresholds [74]. Therefore, there is no
Radicular or neuropathic pain
Musculoskeletal pain: aching,

consensus on differences in pain thresholds between patients with

Radicular/neuropathic pain

cramping, arthralgic, joint

PD and controls due to the controversial nature of current findings

tingling, bizarre quality
Dystonia-related pain

resulting from differences in the studies’ methodologies. In addi-

Musculoskeletal pain
Classification of pain

tion, similar conclusions are reported in relation to the effect of

administration of L-dopa in sensory thresholds since some studies
Dystonic pain
Central pain

reported increased pain thresholds after the administration of L-

dopa, whereas others have reported no changes in pain thresholds
after L-dopa administration (Table 2).
Indeed, Dellapina et al. have demonstrated that treatment with
apomorphine did not also modify pain thresholds or pain-induced
cerebral activity in patients with PD when compared to placebo,
24% two type pain
53% one type pain

suggesting the possibility that monoamine systems other than

Rate of pain

dopaminergic systems are involved in pain modulation [75]. The

lack of an effect of apomorphine to treat PD-related pain suggests
Assessment of Neuropathic Symptoms and Signs; STAI-TX: Stait Trait Anxiety Inventory.

that dopamine agonists may not be as effective as L-dopa in the

VAS, LANSS, STAI-TX 1 and 2 65%

treatment of pain [75]. Therefore, future studies are required to

further determine the role of dopamine agonist drugs in the
management of pain in PD.
SF-36 Bodily Pain Scale,
Brief Pain Inventory

3.4. Factors potentially affecting pain in Parkinson’s disease (PD)

Pain evaluation

The presence of pain in PD is usually dependent of motor

problems e.g., rigidity, tremor, akinesia, or postural abnormalities.
In this section, we explore possible factor influencing the presence
of pain in PD.
(146 pain, 30 no pain)
(90 female, 86% male)

(42 female, 54 male)

3.4.1. Age
Number subjects
176 PD patients

96 PD patients

If we consider the mean age of this patient population, an

increase in the prevalence of musculoskeletal pain with joint
problems and degenerative changes elsewhere in the body would
seem to be expected. However, evidence surrounding this is
controversial. In the study by Goetz et al. patients with pain were
younger than those without pain [48]. Defazio et al. reported that
Hanagasi et al. [53]
Table 1 (continued )

dystonia-related pain was observed at earlier ages [52]. Nègre-

Beiske et al. [8]

Pagès et al. also observed that PD-related pain was seen at an earlier
age than pain unrelated to PD [51]. Studies reporting the absence of
correlation between age and pain have also been published
Author

[8,50,56]. It is important to note that age has not systematically

been considered in all studies and the correlation between the
Table 2
Pain assessment in Parkinson’s disease (PD).
Year Study design
Djaldetti et al. [59] 2004 Group 1: 36 hemi-PD patients (13 female, 23 male, 62
years old, disease duration 5.3, H&Yahr 1e2.5, UPDRS
III: 22.5  14.8, 21 with pain e VAS score was
48.9  24.1)
Group 2: 15 patients with fluctions (65 years, 12 female,
3 male, disease duration 10.6, UPDRS III: 27.8  17.2, 12
patients with pain - VAS score 55.7  21.43)
Control group: 28 age-matched controls (58.9  6.6
years; 16 women and 12 men)
Brefel-Courbon et al. [20] 2005 Group: 9 PD patients without pain (6 male, 3 female, 65
years, disease duration 9.6, Hoehn and Yahr 2e2.5,
UPDRS II OFF: 25  9, on: 15  7)
Control group: 9 healthy controls (6 male, 3 female,
age: 59 years)
Gerdelat mas et al. [45] 2007 Group: 13 PD patients without pain (4 female, 9 male,
age: 62 years, disease duration 7.3 years, UPDRS ON:
10.8  8.8, UPDRS OFF: 21.2  11.8)
Control group: 10 healthy controls (4 female, 6 male,
age: 58 years)
Vela et al. [68] 2007 Group: 50 PD patients (34 male, 16 female, age: 66
years, disease duration 8.0 / 25 patients without
dyskinesia (UPDRS: 19.95  9.16, H&Y 2.28  0.68 and
25 patients with dyskinesia (UPDRS: 24.56  8.35, H&Y
1.88  0.50)
Control group: 25 controls (12 male and 13 female, 62
years)
Lim et al. [46] 2008 Group stable responders: 12 PD patients (8 male, 4
female, age 68 years, duration 3  1 years, UPDRS III
OFF: 30  3, UPDRS III ON: 26  3)
Group fluctuators: 15 PD patients (7 male, 8 female,
age 64 years, duration 3  1 years, UPDRS III OFF: 27  3,
UPDRS III ON: 21  3)
Group dyskinetics: 23 PD patients (13 male, 10 female,
age 63 years, duration 6  1 years, UPDRS III OFF: 31  3,
UPDRS III ON: 19  2)
Control group: 23 age and sex matched healthy
subjects
Nolano et al. [15] 2008 Group: 18 PD patients (9 male, 9 female, age: 62.7 years,
H&Y: 2.6  1.1, UPDRS III 26.6  10.2)
Control group: 30 age- and sex-matched healthy
subjects (61 years old)
Mylius et al. [69] 2009 Group: 15 PD patients (8 patients with pain (PDP), 7
without pain (PDN), 6 female and 9 male, 63 years,
duration 11.0  5.4 years, UPDRS III 28.3  9.4, H&Y
2.3  0.7)
Control group: 18 control subjects (11 female and 7
male, 67 years old)
Assessment methods for pain threshold
Tactile thresholds by using von Frey
filaments
Warm sensation and heat pain thresholds
(HPT)
Evaluation: before taking their first
daily medication for all group
Group 2: assessment in ON and OFF
period
Cold pain threshold (CPT) right hand by
immersion in cold water (temperature:
from 20  C to 0  C, reduced to 3  C by
3  C)
Hand temperature was measured by
using skin thermometer in OFF and ON
periods
The nociceptive flexion reflex (RIII reflex)
All subjects were evaluated in ON and
OFF condition
Pressure pain threshold (PPT) was
evaluated during ON period
Cold pain threshold (CPT): first right
hand and later left hand was immersed
in an ice-water bath (water
temperature 1.0e2.0  C) until subject
felt “faintly painful”
To determinate “cold pain tolerance” the
hand was kept immersed until it
became ‘‘intolerable’’ or 180 s had
elapsed
Pain thresholds were evaluated in ON
condition
Tactile threshold: Semmes-Weinstein
monofilaments
Mechanical pain perception: calibrated
monofilament, with a bending force of
95 mN
Thermal thresholds (cold, warm, cold
pain and heat pain thresholds)
All pain threshold tests were performed
during ON condition.
The nociceptive flexion reflex (NFR)
Electrical pain threshold (EPT)
Heat pain thresholds (HPT)
Body part evaluated
Bilateral forearm
Right hand
Right leg
The dorsal side of the proximal
phalanx of the second finger
and brachioradialis muscle
Right and left hand
The dorsum of the hand and
foot of the less affected side in
PD patients
Left or right calf
Results
Mechanical and warmth sensory thresholds
equal in groups
Heat pain thresholds:
PD patients HPT < control subject
PD patients with pain HPT < PD patients
without pain
More affected side HPT < less affected side
OFF: pain threshold in PD patients < controls
ON: pain threshold in PD patients ¼ controls
Levodopa response: pain threshold during OFF
period in
PD patients < pain threshold during ON period
A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294
OFF: PD patients < healthy subjects
ON: PD patients ¼ healthy subjects
Levodopa response: pain threshold during OFF
period in
PD patients < pain threshold during ON period
PPT was similar for three groups all body part
Women had lower PPT than men
CPT and tolerance (OFF) Healthy > PD patients
After levodopa administration dyskinetic
patients exhibited a large increase in CPT and
tolerance that was absent in stable responders
Tactile threshold: PD patients > control subjects
Mechanical pain perception: PD
patients < control subjects
Thermal thresholds (cold, warm, cold pain and
heat pain):
PD patients > control subjects
NFR: PD patients < control subjects/PDN ¼ PDP
patients
EPT: PD patients < controls PDN ¼ PDP patients
HPT: PD patients < control subjects/PDN ¼ PDP
patients
(continued on next page)
291
 292 A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294

different kinds of pain with age has not been investigated in some

-Pain threshold: PD patients < control subjects

-Pain tolerance: PD patients < control subjects

studies.

subjects (hand) PD patients > controls (Feet)

-Tactile threshold: PD patients ¼ control 3.4.2. Gender
Current thinking tends to favor the absence of gender differ-
ences in relation to the presence or absence of pain [48,50e53];
however, Beiske et al. reported that female gender was a significant
PD OFF ¼ healthy controls
PD ON > healthy controls

predictor of pain in PD [8]. Scott et al. also observed that male and
female patients do not complain of pain in the same locations, since
women reported higher prevalence of neck and low back pain than
PD ON ¼ PD OFF

men [49]. Vela et al. [68] found lower pressure pain thresholds in
women. A link between pressure pain thresholds and musculo-
skeletal pain has been described [76], leading to the suggestion that
Results

(both)

(both)

mechanical sensitivity is higher in women.

3.4.3. Severity and duration of the disease

and to the big toe of each foot
(proximal, middle, and distal)
Volar surface of each forearm

The little finger of each hand

The effect of severity and duration of disease on pain is

controversial. Nègre-Pagès et al. observed a correlation between
PD-related pain and the severity and duration of disease [51].
Body part evaluated

Similarly, a longer duration of disease and greater motor compli-

cations in patients with PD with pain have been reported as
compared to pain-free patients [50,77]. Other studies have not
found this correlation [8,52,53].

3.4.4. Depression
Symptoms of depression can be observed in PD patients,
conditions and twice in healthy subjects

pain tolerance were measured by using

Assessment methods for pain threshold
VAS (pain) 1 e For pain: 0e200 mm: 0

Tactile threshold, pain threshold, and

ranging in intensity from mild to severe [78]. Considering that

e100 mm thermal sensation, 100

chronic pain is a risk factor in the development of depression in

HPT was assessed in ON and OFF

the elderly [79,80] and the older age and complications of PD

e200 mm painfull sensation

patients, a link between depression and pain seems probable.

Depression has been generally evaluated in studies of pain. Goetz
et al. reported that pain intensity correlated with depression, and
electrical stimuli.

that the latter is more severe in patients experiencing pain than

in those without pain, even though the incidence of depression
was the same in both groups of patients [81]. Starkstein et al.
observed that pain was more frequent in patients with major
depression as compared to those with milder depression [82].
Similarly, a link between pain and depression in PD has been
Group: 106 PD patients (66 with pain, 40 without pain,
Group: 12 PD patients (10 male, 2 female, age: 60 years,

Control group: 51 healthy control subjects (36 male, 15

Control group: 13 control subjects (7 male, 6 female,

reported by Ehrt et al. [77] and McNamara et al. [1]; however,

70 years, 59 male, 47 female, duration of disease: 5.7
duration 9.4  3.2, UPDRS ON 15  10.9, UPDRS OFF

years, H&Y: 2.1  0.9, UPDRS III OFF: 23.5  13.6)

others have not shown a correlation between pain and depres-

sion [50,53]. Current evidence suggests that depression is
a parameter to be considered in studies of pain in patients with
PD, considering the frequency of depression in PD and the fact
that it can modify the perception of pain and it can be also
properly treatable.

3.4.5. Systemic disease and pre-existing disturbances

Patients with pre-existing pain related to systemic diseases such
female, age: 69 years)
62.9  8.3 years old)

as diabetes, osteoporosis, rheumatic disease, and age-dependent,

e.g., joint or disc disease or postural problems, will continue to
Study design

experience these after diagnoses; however, new disease related

28.8  9.4

symptoms, such as rigidity, akinesia, muscular cramps, and postural

instability can worsen these difficulties. Beiske et al. reported that
some patients complained of pain before the diagnosis of PD [8].
The results reported by Defazio et al. showed that joint pain and
2011
2010
Year

peripheral neuropathic pain is seen in controls matched for age

with PD patients [52]. These studies support the theory that some
pain seen in patients with PD is related to age rather than the
Nandhagopal et al. [72]

disease itself.
Marsala et al. [71]
Table 2 (continued )

The pain experienced by the patients prior to PD diagnosis could

be one reason for the controversial character of the findings
regarding the incidence of pain in PD. Several studies had generally
evaluated the presence of pain in a cross-sectional design, without
indicating if the complaints started before or after the diagnosis of
PD. On the other hand, such pain could also be related to the
 A. Fil et al. / Parkinsonism and Related Disorders 19 (2013) 285e294
disease, but appearing much earlier than the diagnosis [83].
Controlled studies in large patient populations defining the time at
which the pain started and investigating it in detail according to its
different types are more than needed.
3.5. Pain and quality of life
Pain clearly affects the quality of life (Quol) of PD patients. A
link between pain, sleep problems and depression has been
described [81,84]. The interactions among these conditions
increase and complicate the problem by creating a vicious circle.
Some studies report that pain and other related conditions
negatively impact Quol in PD patients [85,86]. Barone et al. found
that non-motor disturbances negatively influence Quol and that
leg pain occupies third place in order of importance [87]. Politis
et al. examined the impact of PD from a patient’s perspective [88].
They classified patients into two groups according to the duration
of disease: early (<6 years) and late (>6 years), and asked them to
determine their problems in order of importance. Pain was one of
the most frequent non-motor problems in both groups. The early
PD patient group complained of musculo-cutaneous pain first and
visceral pain second, whereas the late PD group listed musculo-
cutaneous pain in first place, but dyskinetic and dystonia-related
pain second [88].
4. Conclusions
Pain in PD is likely related to pathologic changes in the
anatomical structures involved in nociceptive pain mechanisms.
Most studies on pain mechanism in PD have been conducted in
animals. Pain, one of the most frequent non-motor symptoms
affecting PD patients has complicated mechanism and is influenced
by several factors, e.g., age, gender, depression, severity, or duration
of the disease. Further, there are many methodological differences
among the studies aimed at classifying pain and characterizing its
subtypes. The fact that the patient population includes mostly the
aged increases the number of factors involved. There are also
problems with the studies investigating pain thresholds and
perception, as different studies follow different protocols and
consequently have different outcomes. There is a need for multi-
center studies with a large number of patients and controls, in
which patients should be evaluated in different dimensions for
measurable endpoints to acquire definitive data and open new
directions for treatment, of the pain so often present in patients
with PD.
Conflict of interest
The authors declare no conflicts of interest.
1) No funds were received for this study; 2) No financial benefits
have or will be derived by the authors from this study; 3) The data
from this study have not been presented in any other form.
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