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Chapter 29Pain and Paresthesia in Parkinson’s Disease

Shen-Yang Lim1 & Andrew H. Evans2

1Faculty of Medicine, University of Malaysia, Kuala Lumpur, Malaysia2Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria and Department of Medicine, University of Melbourne,Australia

Introduction

Charcot noted in 1877 that “paralysis agitans is not onlyan extraordinarily sad disease in that it robs patients ofthe use of their limbs . . . it is also a cruel disease sinceit causes distressing sensations.” Pain is defined as anunpleasant or distressing sensory experience, whereasparesthesias are abnormal (usually non-painful andsuperficial) sensations. Pain is a frequent complaint inParkinson’s disease (PD) patients. It adversely affectshealth-related quality-of-life [1,2], and in a minority ofpatients may even overshadow the motor symptomsof PD [3–5]. It interferes with the ability of patientsto participate in their activities of daily living [6], forexample, by further impairing mobility [7,8]. Pain cancontribute significantly to sleep disturbance due tofrequent awakenings [9]. Major depression is much morecommon in patients with pain compared to those without[9]; some patients have even considered suicide becauseof their pain [10]. In many patients, pain is also associatedwith anxiety and even panic [11]. Conversely, it has beenreported that paresthesias, which are often intermittent,are generally easily tolerated by patients and may notadd to parkinsonian disability [12]. In this chapter, wedescribe the epidemiology, clinical features, and mech-anisms of sensory (mainly pain) syndromes in PD, andprovide a framework for evaluating and treating thesesymptoms.

Epidemiology of sensory symptomsin PD

The prevalence of sensory complaints in PDSensory or painful syndromes affect approximately two-thirds of PD patients (Table 29.1). In studies where anattempt was made to determine the etiology of painfulsymptoms, between 29 and 63% of PD patients were

thought to have pain directly related to PD. Incidentally,pain is also reported by about half of patients with mul-tiple system atrophy (MSA) [13], and is more commonin MSA-P (predominantly parkinsonian subtype) than inMSA-C (predominantly cerebellar subtype) [14].

Studies comparing pain in PD patients toage-matched controlsOlder age is associated with an increased propensityfor painful conditions (e.g., rheumatologic/orthopedic)[15,16]. Studies of elderly people have found that about70% experience pain [15,17]. However, in PD pain doesnot relate to older age [1,6,16,18–20] and is more preva-lent – and more severe [1,2,16] – compared with age-matched controls. Karlsen et al. found that 67% of PDpatients reported pain problems compared with 39% ofhealthy elderly controls matched for age and sex [21].Riley et al. surveyed 150 consecutive PD patients and 60age- and sex-matched controls and found a higher inci-dence of frozen shoulder in the PD group (13% versus 2%)[22]. Etchepare et al. reported a 60% point prevalence ofthoracic/lumbar back pain in a group of 104 PD patientscompared with 23% in a matched control group of chroni-cally ill patients [16]. Radicular symptoms including painare also more common in PD patients than non-PD neu-rologic controls (36% versus 11%) [23].

Gender differencesWith a few exceptions [24,25], no gender difference inthe frequency of pain complaints has been found inPD patients [6,8,18,26,27]. Burning mouth syndrome wasreported to be 1.7 times more common in women patients[28]. and genital pain may also be more common inwomen [29].

Pain in early- and later-stage PDWith a few exceptions [2,30], no correlation has beenfound between the presence or severity of pain and

Parkinson’s Disease: Non-Motor and Non-Dopaminergic Features, First Edition. Edited by C. Warren Olanow, Fabrizio Stocchi, and Anthony E. Lang.c© 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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Table 29.1 Frequency of sensory complaints in PD: unless noted otherwise (see footnotes), these were studies of patients attendingmovement disorders clinics.

Frequency of sensory symptoms (%)

Study Sample size Overall Unrelated to PD PD-related Definition used

Snider et al. [24] 105 – 4 43h Primary sensory symptoms (i.e., without an apparentsomatic cause; patients with arthritis or diabetesexcluded; painful muscle spasm or cramps secondaryto sustained muscle contraction also excluded)

Koller [12] 50 – – 38i Primary sensory symptoms (patients withmusculoskeletal disease or diabetes excluded)

Goetz et al. [6] 95 – – 46 Pain that patients believed was directly related totheir PD

Karlsen et al. [30]a 233 67 – – Pain dimension of the Nottingham Health Profile

Honey et al. [112]b 50 – – 42 Pain attributable to PD

Shulman et al. [149] 99 – – 63 Commonly experienced pain, numbness, tingling, orburning in association with PD

Vela et al. [27] 50 64 – – Pain

Quittenbaum and Grahn [1]c 55 68 – – Aching/pain during the last month

Mott et al. [25]d 444 64 – – Pain

Giuffrida et al. [18] 388 67 – – Sensory or painful syndromes

Lee et al. [19] 123 85 64 63 Pain

Tinazzi et al. [20] 117 40 – – Pain (duration ≥2 months)

Martinez-Martin et al. [224] 545 – – 29 Unexplained pains (not due to known conditions suchas arthritis)

(NMSQuest)

da Silva et al. [8] 50 56 – – Pain

Negre-Pages et al. [2]e 450 62 25f 37 Chronic pain (3 months duration)

Lim et al. [84] 50 – – 48g Commonly experienced pain which the patientattributed to PD

aUnselected community-based group of PD patients.bPatients with medically refractory motor features presenting for pallidotomy.cCounty hospital neurology clinic.dPD support group members.eGeneral neurological practice.f Mainly osteoarthritis.g2/12 (17%) of the stable responders, 9/15 (60%) of the fluctuators (without dyskinesia), and 13/23 (57%) of the dyskinetic patients.hPain 29%; tingling 22%; numbness 21%; burning 11%.i Numbness 24%; tingling 16%; pain and achiness 12%; coldness 12%; burning 2%.

disease duration or disease stage (as measured by theseverity of motor features) [6,8,16,18–20,31]. The fre-quency of pain complaints in PD is thought to have abimodal distribution [8,18]. There seems to be an initialpeak of painful symptoms prior to or at the onset of PD[18]. For example, Riley et al. found that the peak inci-dence of frozen shoulder was during the 2 years prior tothe onset of other clinical symptoms (11/19 cases) [22].In many patients, pain resolves with initiation of anti-parkinsonian treatment [3,8,22].

A second peak occurs later in the disease course, inconjunction with the development of motor fluctuations

and dyskinesia [11,20], and possibly also as a consequenceof accumulating PD pathology. For example, one studyusing multivariate analysis found that PD patients withpain had an odds ratio of 5.7 of having motor responsecomplications (MRCs) compared with those without pain[20]. Other investigators have reported similar findings[2,25,27]. Further indirect support for a link between MRCand pain phenomena is that PD patients with chronicpain have younger age [6] and younger disease onset [2].MRCs are also strongly linked to younger age of PD onset[32,33]. Furthermore, pain is also more commonly experi-enced by MSA patients with MRC (relative risk 1.63) [13].



Pain and Paresthesia in Parkinson’s Disease 317

Table 29.2 Relative proportions of sensory symptoms in PD.

Pain type Goetz et al. [6] Honey et al. [112] Giuffrida et al. [18] Tinazzi et al. [20]

No. of patients with sensory symptoms 43 21 269 47

RheumaticMusculoskeletal 74% 76% 94% (“muscular”) 47%

Joint – – 51% (“osteoarticular”) –

Somatic pain exacerbated by rigidity orinvoluntary movements of PD

14% 29% – –

Dystonic pain 28% 19% – 66%

Radicular/neuritic pain (localized to theterritory of a nerve root or nerve)

14% 0% 8% (localized or less-defined“neurogenic” pain)

9%

Primary parkinsonian (central) pain 0% 10% (“dysesthetic” pain –poorly localized, burning)

4%

Akathitic discomfort 2% – 10% (akathisia or RLS) –

RLS – – –

The following case example, taken from a series byRiley and Lang (patient 1) [34], illustrates a pattern thatis not infrequently encountered in clinical practice. A 62-year-old woman had a 3 year history of pain and stiff-ness in her neck and upper back, which had been diag-nosed as “fibrositis.” When signs of parkinsonism werefound 3 years later, and l-dopa commenced, she experi-enced a marked improvement of her motor function andsoon became pain free for the first time in years. How-ever, she developed dyskinesia and motor response fluc-tuations. She had pain, where the skin over her legs feltextremely sensitive “like a fresh sunburn,” together withpronounced parkinsonism and episodic severe depres-sion each time her medication wore off. The “off” periodpain resolved whenever her l-dopa took effect.

Phenomenology of PD-related painThe spectrum of sensory symptoms experienced by PDpatients is wide. Features to consider include the timecourse, location, quality and severity of pain, and impactof anti-parkinsonian medication, including relationshipto motor fluctuations (e.g., “off” period or biphasic dys-tonia or “on” period chorea).

TopographyEvery localization of pain has been described in PD [4],and in some patients the pain may be poorly localized[24,35–37]. The most commonly painful sites are the back,legs, and shoulders [2,19,20,25]. In the majority of cases,the pain occurs on the side more affected by parkinson-ism [12,20,22,24,37,38]. Pain may adopt unusual distribu-tions, such as a “pseudoradiculopathy” (radiating fromthe hip or shoulder down the affected limb) [3,39], oral(tongue, palate, lip or gum), or genital pain syndromes[28,29], chest pain [3,11], and upper or lower abdominal

discomfort [3,11]. Apart from occasional cases of painfuldystonic spasms involving the neck and jaw, headachesand facial pain syndromes are relatively rarely encoun-tered in PD patients [3,18].

Clinical features

Quality/categorization of sensory symptomsDiscomforting sensations encompass a range of symp-toms and include aching, cramping, stiffness, numbness,tingling, burning, coldness, and itching, and may beaccompanied by motor restlessness [12,18,24]. A classifi-cation of sensory symptoms is given in Table 29.2. Pub-lished series are in general agreement on the prevalence ofsensory symptoms in PD, but there is less consistency onthe proportion of patients in each of the various categories.In contrast to the study by Goetz et al. (where pain wasalmost completely accounted for by somatic pain, due tomusculoskeletal disease or dystonia) [6], other investiga-tors have found high rates of “primary” sensory symp-toms (see Table 29.1 – Snider et al. and Koller et al.). Thisdiscrepancy is no doubt at least partly accounted for bydiffering definitions of “central” or “primary parkinso-nian” sensations. Ford described this type of painful sen-sation as follows: “Burning, tingling, formication; relent-less, bizarre quality; location not confined to root or nerveterritory; not explained by rigidity or dystonia; may fluc-tuate with medication effect” [4]. However, given that PDpatients typically demonstrate hyperalgesia, it could beargued that a “central” component may be involved inmost if not all types of pain experienced by PD patients.One may see patients whose pain has a clear nociceptivebasis (e.g., secondary to lumbar disc herniation), but isaggravated during “off” medication periods [40].



318 Chapter 29

Pain severityUsing a pain severity scale of 0–100, patients in the studyby Goetz et al. reported a mean pain score of 56 [6]. Ina study by Lee et al. using similar methodology, meanpain score was 39 (median 37) [19]. Significantly, 50% ofpatients in this series said their pain was moderate ordominating their day.

Fluctuations in relation to the L-dopa cyclePain fluctuates with parkinsonian disability in one- totwo-thirds of PD patients [6,18], and usually (in almost90% of cases) occurs in the motor-“off” phase (with orwithout dystonia) [5,6]. Less commonly, patients identifypain in the “off”-to-“on” (beginning-of-dose) switch, dur-ing l-dopa’s peak effect, or at the time of the “on”-to-“off”(end-of-dose) switch [3,5]. Some patients report that themost incapacitating type of fluctuations (motor or non-motor) is the sensory ones [5].

Dystonic painPainful dystonic spasms tend to occur in the limbs mostaffected by parkinsonism [41] and are often accompa-nied by visible dystonia [6]. The toes and feet are mostlyinvolved (e.g., inversion of the foot, toe curling, exten-sion or flexion of the big toe), but dystonic pain can alsoinvolve the neck or jaw [39,41]. Dystonic pain is morecommon in the “off” phase [41]. but in patients withbiphasic dyskinesia it can be most distressing at the begin-ning or end of dose [3,42]. The prevalence of dystonia cor-relates with the duration of dopaminergic treatment, butyounger patients may occasionally experience it as theirfirst motor symptom [41,43,44].

Neurobiology of painPain may be categorized etiologically as nocicep-tive/inflammatory or neuropathic (also called neuro-genic). Nociceptive pain is triggered by tissue injury;examples include arthritis and visceral pain. On the otherhand, neuropathic pain is caused by damage to or dys-function of the (central or peripheral) nervous system[45]. Causes of central neuropathic pain include stroke,multiple sclerosis, and PD [46]. Patients with neuro-pathic pain may report combinations of spontaneous (i.e.,stimulus-independent) pain and abnormal evoked pain(termed “allodynia” when triggered by normally innocu-ous stimuli, and “hyperalgesia” when it is an exagger-ated response to a stimulus that would normally causepain) [47]. The basic categorization into nociceptive ver-sus neuropathic pain – although not always straightfor-ward [48,49] – may have clinical significance; for example,neuropathic pain may not respond as well as nociceptivepain to nonsteroidal anti-inflammatory agents or opioids,but can be more effectively treated by drugs that modu-late nervous system function [47,50,51].

Ascending pathwaysNociceptive information is carried from peripheral painreceptors by small-diameter Aδ and C fibers. Upon enter-ing the gray matter of the spinal cord, these axons synapsemainly in layers I (marginal zone) and V of the dor-sal horn. Second-order sensory neurons then cross overin the spinal cord anterior commissure to ascend in thespinothalamic tract (Figure 29.1). The main relay for the

Figure 29.1 Central pain pathways. For clarity, the mesolimbicdopaminergic projection from the ventral tegmental area to thenucleus accumbens has been omitted. Abbreviations: A11 = A11cell group in the dorsal hypothalamus/caudal thalamus; ACC =anterior cingulate cortex; DH = dorsal horn of spinal cord; LC =locus coeruleus; PAG = midbrain periaqueductal gray; PbN =parabrachial nucleus; RVM = rostral ventral medulla; SM =spinomesencephalic; SR = spinoreticular; ST = spinothalamic.




spinothalamic tract is the ventral posterior lateral nucleus(VPL) of the thalamus, which in turn relays somatosen-sory inputs to the cerebral cortex. In addition, thespinothalamic tract projects to intralaminar thalamic andmedial thalamic nuclei; these projections, together withthe spinoreticular tract (projecting to the parabrachialnucleus and locus coeruleus) are probably responsiblefor mediating the emotional and arousal aspects of pain[52–54]. The spinomesencephalic tract projects to themidbrain periaqueductal gray (PAG). Together, theseascending (spinothalamic, spinoreticular, and spinomes-encephalic) pathways make up the anterolateral system.

Central modulation of painBrainstem-descending pain-inhibitory pathways includethe PAG, which inhibits pain transmission in the dorsalhorn via a relay called the rostral ventral medulla (RVM)or nucleus raphe magnus (part of the raphe nuclei ofserotonergic neurons), and the A5 and locus coeruleuscell groups in the pontine tegmentum (which send nora-drenergic projections to the dorsal horn) [50,55]. Higherorder cerebral structures receive and integrate nocicep-tive information to regulate behavior and are also poten-tial sources of (direct and indirect) influence on nocicep-tive processing in the dorsal horn [52,55]. There may beinputs, for example, to the PAG from pain-related corticalareas such as the somatosensory areas, the insular cortex,and anterior cingulate cortex (ACC) [52,55]. Other subcor-tical sites that may play a role in pain modulation includethe nucleus accumbens (NAcc) (and other nuclei of thebasal ganglia) [26,56,57–59], thalamus [56], hypothalamus(e.g., diencephalospinal dopaminergic pathway, project-ing – uncrossed – from the dopaminergic A11 cell group inthe dorsal hypothalamus/caudal thalamus to the dorsalhorn at all spinal levels) [42,60–63], amygdala [55–57,64],and cerebellum [65]. For example, mesolimbic dopamin-ergic neurons projecting from the ventral tegmental area(VTA) to the NAcc form part of a potent pain-suppressionsystem; enhanced dopamine release from terminals inthe NAcc triggered by stress or noxious stimuli has beenshown in animal studies to result in suppression of tonicpain of similar magnitude to high-dose morphine [66,67].

Dimensions of pain experiencePain experience results from a complex integration ofsensory-discriminative (e.g., perception of location andintensity of pain), affective–motivational (e.g., feelings ofunpleasantness, with motivational properties of escape),cognitive–evaluative (e.g., learning to avoid similar stim-uli in the future), and autonomic–neuroendocrine (e.g.,induction of flight or fight responses) processes [53,68].These different dimensions of the pain experience aremediated by different areas of the brain [52,69,70]. Forexample, activation of the lateral thalamus and S1/S2somatosensory cortex seems to be preferentially associ-

ated with the sensory-discriminative aspect of pain. Theintralaminar thalamic and medial thalamic nuclei, ACC,and anterior insular cortex (components of the limbic sys-tem) are more involved in the affective–emotional aspectof pain [52,69,70]. Systems mediating affective aspects ofpainful experiences overlap with limbic systems function-ally mapped to a range of affective disturbances. Humanbrain imaging investigations of anxiety, fear, dyspho-ria, depression, and pain, and studies involving expo-sure to pleasant or unpleasant images, music, touch, ortaste, have all implicated the subcallosal anterior cingu-late region (BA 25) [71–78]. Medial temporal and pre-frontal areas may be related to more cognitive aspectsof pain, and structures such as the insular cortex, amyg-dala, hypothalamus, and brainstem nuclei are involved inthe autonomic response to painful stimulation [52,53,55,79–81]. There is a growing literature on the extensiveinteractions between the nociceptive and autonomic ner-vous systems at all levels of neuraxis, which has beenreviewed elsewhere [81–83].

Mechanisms of PD-related pain

The etiologic basis of PD-related pain is multifactorial,with varying degrees of contribution from peripheral(motor/mechanical) and central sources (Figure 29.2).Central mechanisms include derangement of intrinsicpain-modulating (i.e., anti-nociceptive) monoaminergicsystems [50], in addition to plastic central nervous sys-tem (CNS) changes induced by chronic anti-parkinsonianmedication treatment [20,84].

CNS pathology of PDAlthough the pathology of PD is defined by neuronalloss in the substantia nigra, there has been increasing

Impairment ofintrinsic anti-

nociceptive systems(e.g. dopaminergic,

noradrenergic,serotonergic deficits)

Peripheral(motoric/mechanical)

problems(e.g. dystonia, rigidity,

abnormal posture)

PD medication-induced plastic

changes in the CNS

PD-related

pain

Figure 29.2 The etiological basis of PD-related pain ismultifactorial, with varying degrees of contribution fromperipheral and central mechanisms.



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Table 29.3 Pain-processing structures involved in PD. PAG =midbrain periaqueductal gray.

Structures Braak stage

Spinal cord lamina I 3, possibly earlier [83]

Lower brainstem (e.g., locus coeruleus,raphe nuclei)

2 [88]

Upper brainstem (e.g., PAG, parabrachialnucleus, pedunculopontine nucleus)

3–4 [88,225–228]

Hypothalamus 3 [88]

Thalamus (especially medial thalamic andintralaminar nuclei)

4 [86–88]

Limbic structures (e.g., amygdala, insula,anterior cingulate gyrus)

3–4 [88]

recognition of the pathologic changes that also occur in arange of extra-nigral sites in both the central and periph-eral nervous systems [85], including many of the struc-tures discussed above that are important in pain pro-cessing (Table 29.3). Lesions or dysfunction of systemsthat under normal conditions transmit noxious informa-tion from the dorsal horn of the spinal cord to the cere-bral cortex can lead to central pain [46]. It has been sug-gested that the incidence of central pain is highest withlesions in the dorsal horn, followed by lower brainstemand thalamic lesions, regions that are consistently involvedin PD [83,86–88]. However, clinico-anatomic studies arelacking and the precise anatomico-pathologic substratesfor central parkinsonian pain remain speculative. Con-duction along peripheral and central pain pathways, astested by laser stimuli (selectively activating pain recep-tors in the skin, and recording laser-evoked potentialsover the scalp), is normal in PD patients with primarycentral pain [37]. A peripheral neuropathic componentis unlikely, given the absence of pathologic findings inperipheral somatosensory nerves [24]. Although there arecase reports of peripheral neuropathy in juvenile PD (e.g.,due to Parkin disease), this entity is clinically distinct fromsporadic/idiopathic PD [89,90].

Pain due to central dopaminergic deficiencyTreatment of PD patients with dopaminergic agents maybe dramatically effective in alleviating pain. Furthermore,experiments using evoked pain have found reduced painthreshold and tolerance (i.e., allodynia and hyperalgesia)in PD patients compared with non-PD subjects [84,91,92].One study also found a lack of habituation of sympa-thetic sudomotor responses to repeated pain stimuli inPD patients with primary central pain (suggesting anautonomic hyper-reactivity to pain inputs) [37]. Theseabnormalities are more prominent in patients reportingspontaneous pain [37,91,93], and on the side with worseparkinsonism [37,84,91]. The importance of dopaminer-

gic deficit as a causal factor in PD-related pain is impliedby the normalization of these abnormalities after l-dopaadministration seen in most [37,84,92,94,95], although notall [91,96], studies. Moreover, a PET study demonstratedthat overactivation of cortical areas involved in process-ing sensory-discriminative and affective–motivationaldimensions of pain in the untreated state is reduced afterl-dopa administration [92]. A role for dopamine in painmodulation is further supported by observations thatfar more patients with parkinsonism induced by neu-roleptics (dopamine receptor blockers) report pain com-pared with patients receiving other psychotropic medi-cations [97], and dopaminergic therapy has been used totreat a variety of painful conditions in non-PD patients,including chronic thalamic pain [98], burning mouth syn-drome [99], restless legs syndrome [100], diabetic neu-ropathy [101], fibromyalgia [102], and metastatic can-cer [103]. Some authors have found that the analgesiceffect of l-dopa may be dose dependent [94,104]. Thesite of action of exogenously administered dopamine hasbeen hypothesized to involve the mesolimbic system [84].Other possible sites of dopamine-mediated inhibition ofnociceptive activity include the thalamus [105–107] anddiencephalospinal pathway [42,60–63].

Non-dopaminergic mechanismsNevertheless, there remains a majority of patients with PDin whom initiation or modification of dopaminergic ther-apy does not abolish pain. This includes de novo patientsin whom dopaminergic therapy ameliorates parkinson-ism (i.e., the motor disorder) [35], and even patients inwhom motor and sensory symptoms fluctuate in responseto l-dopa (i.e., these patients do not obtain pain relief withadditional administration of l-dopa) [50]. In an experi-mental setting (after overnight withdrawal of PD medica-tions), we found reduced pain intensity and unpleasant-ness in 42% of 50 patients following the administration ofa dose of l-dopa [in 17% of the stable responders, 53% ofthe fluctuators (without dyskinesia), and 48% of the dysk-inetic patients; differences between groups did not reachstatistical significance] [84]. In a series by Djaldetti et al.,spontaneous pain responded to l-dopa challenge in only20% (3/15) of fluctuating patients [91]. In other studies,only 28% of (surveyed) patients reported that PD medica-tion relieved their pain [8,27] (wearing-off and dyskinesiapresent in 53% and 25% of patients in the latter study).Lee et al. [19] reported that only 10% of pain complaintswere improved by PD medication, and at the end of thespectrum, a study by Giuffrida et al. [18] found that painpresent at the beginning of the disease resolved in only 3%of patients during the course of the disease. The observedlack of response to dopaminergic agents in many patientsis perhaps not unexpected, considering the widespreadinvolvement of non-dopaminergic structures in PD(Table 29.2).




Abnormalities of noradrenergic and serotonergic path-ways descending to the spinal cord are assumed to haverelevance for pain perception in PD [3,50], given that sero-tonin and noradrenaline are the major neurotransmittersin the inhibitory modulation of pain through descendingpathways. Widespread loss of brain serotonergic inner-vation is a feature of PD [108], and reduced serotoninmetabolite [5-hydroxyindoleacetic acid (5-HIAA)] in cere-brospinal fluid (CSF) (thought to indicate impaired cen-tral serotonin metabolism) has been demonstrated innon-depressed PD patients with pain, compared withthose without pain and healthy volunteers [50,93] (CSF5-HIAA is also reduced in depressed PD patients) [109].In a placebo-controlled, double-blinded study, Cantelloet al. reported on the potent analgesic effect of i.v.methylphenidate (which enhances adrenergic and sero-tonergic transmission) in PD patients with a fluctuatingmotor (in addition to pain) response to l-dopa, noting,however, that this effect was abolished by pretreatingpatients with a β-blocker or serotonin antagonist [50].Dopaminergic and non-dopaminergic systems also inter-act; for example, it has been suggested that morphine andcodeine may be synthesized in the body from l-dopa ordopamine [110], and lesioning the nigrostriatal dopamin-ergic system in rats prevents (the normal) tail pinch-induced increases in forebrain serotonin output [111].

Pain directly attributable to the motorfeatures of PD (dystonia, rigidity, chorea,tremor, and postural abnormalities)Dystonic pain is likely to be musculogenic in origin [112].In support of this, Pacchetti et al. reported on the com-plete disappearance of painful foot dystonia in 70% ofpatients treated with botulinum toxin injections into theaffected muscles (the mechanism of analgesia presumablyrelates to reduction of tonic muscle contraction) [113,114].In other patients, pain appears to be secondary to parkin-sonian rigidity in axial or limb muscles [6]. However, thisexplanation does not seem adequate in many patientswith painful complaints, in whom rigidity is often rel-atively minor [24,50]. Three decades ago, Snider et al.found very similar rigidity scores for patients with andwithout sensory symptoms (1.37 ± 0.15 versus 1.31 ±0.14, respectively, scored on a scale of 0 to 4 for increas-ing rigidity), and suggested that the motor deficit of PDaccounts for only a small proportion of sensory symp-toms [24]. The observation that pain usually occurs ipsi-lateral to the limb first and more affected by parkinsonism[12,20,22,24,38] does not necessarily, in our view, argue fora muscular origin. There are some data to suggest thatlateralization of PD pathology may not be unique to themotor (nigrostriatal) system [115,116]. and it is theoret-ically possible that pain systems (e.g., mesolimbic path-way or serotonergic/noradrenergic pathways) [50] in PDmay be more affected ipsilateral to the side with greater

nigral pathology. Supporting this contention are cases inwhich pain precedes ipsilateral development of PD motorsymptoms [12,24,38]. Conversely, there are patients withsevere rigidity who do not have pain [112].

Somatic pain may be exacerbated by repetitive move-ments (dyskinesia or parkinsonian tremor), e.g., neckchorea triggering painful arthritis or cervical radiculopa-thy [3,6,112], or symptoms of median neuropathy sec-ondary to severe tremor [6]. About 50% of patients withradicular/neuritic pain in the series by Goetz et al. relatedthis type of pain to being “on,” although it is not clear ifthis was due to dyskinetic movements. In this series, 85%of patients reported no consistent relationship betweenjoint pain and motor fluctuations.

Postural abnormalities of PD (e.g., stooped posture) maysometimes contribute to pain [6]. In one study, 77% ofpatients with camptocormia (i.e., extreme spinal flex-ion deformity) reported mild-to-moderate low back pain[117]. This could result from paraspinal muscle hyperto-nia [117], or the postural abnormality may cause mechan-ical stress on soft tissues (and contribute to lumbar discherniation) and bone structures [23]. The simple stoopedposture of PD (i.e., not extreme camptocormia) may beenough to exaggerate low back pain in many patients.

Pain due to anti-parkinsonianmedication-induced plastic changesPatients initially treated with dopaminergic medicationsexperience a stable response throughout the day. They donot perceive a change in their parkinsonian symptomsfrom one dose of medication to the next. However, therepeated pulsatile stimulation of striatal dopamine recep-tors inherent in the oral treatment of PD induces plas-tic changes in basal ganglia circuits that can lead to thedevelopment of pharmacologic sensitization and toler-ance [118,119]. Augmentation of motor (and also somenon-motor) responses and the emergence of dyskinesiaare generally considered to be sensitization phenomena[119–122]; in contrast, shortening of the duration of med-ication effect with repeated dopaminergic drug dosingis considered to result from the development of drugtolerance [119]. Because the human striatum also has acentral role in processing nociceptive information [26],we tested the hypothesis that plastic changes may alsooccur in pain responses in patients with dyskinesia andfound that after a standard l-dopa challenge, dyskineticpatients experienced large increases in cold pain thresh-old (48%) and tolerance (66%) that were absent in sta-ble responders (Figure 29.3) [84]. Consistent with thisnotion, parkinsonian monkeys with dyskinesia displaypathologic metabolic activity in limbic and associative-related structures, and not simply in motor parts of thebasal ganglia [123]. In addition to its role in pain mod-ulation, the mesolimbic dopamine system mediates vari-ous aspects of reward and motivation [124]. Neuroplastic



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−30

−20

−10

0

10

% change inthreshold from t1

to t2 % change inthreshold from t2

to t3

% change intolerance from t1

to t2 % change intolerance from t2

to t3

20

30

40

50

60

70

−4

−14 −1

−8−20

−2

−13

−27

37

28

66

48

Fluctuators DyskineticsStable responders

Figure 29.3 Mean percentage change in threshold and tolerancefrom t1 to t2, and from t2 to t3 in the stable responder, fluctuator,and dyskinetic groups. For clarity, error bars have been omitted,but are given as follows (mean ± standard error, from left to right,starting from the front row: –4 ± 11, –14 ± 5, –1 ± 10, –2 ± 5, 37 ±19, 28 ± 18, –8 ± 11, –13 ± 8, 48 ± 12, 66 ± 20, –20 ± 7, –27 ± 6).

Asterisks (∗) indicate significant differences between thedyskinetic and stable responder groups according torepeated-measures ANOVA and post hoc t-tests. t1, 12 h offdopaminergic medication; t2, full “on” state at least 60 min afterl-dopa; t3, 6 h post-l-dopa.

changes within this system were recently demonstrated ina group of PD patients compulsively overusing dopamin-ergic drugs and exhibiting disabling dyskinesia [125].Taken together, we postulated that the increased painthreshold and tolerance observed in dyskinetic patientswhen “on” may reflect a process of sensitization to theanalgesic and motivational effects of l-dopa [84].

It is intriguing to consider the possibility that intermit-tent administration of dopaminergic drugs that have anal-gesic effects may lead to a hyperalgesic state and predis-pose PD patients with dyskinesia to chronic pain in thesame way that administration of opioids can sometimesparadoxically aggravate pain (the phenomenon of opioid-induced hyperalgesia) [126–128]. The motivational effectsof drug withdrawal are central to negative reinforcementmodels of addiction in which the motivation to compul-

sively use drugs of addiction is driven by a desire to avoidthe aversive affective state associated with withdrawal[129–131]. According to this theory, the acutely rewardingproperties of psychostimulant drugs inevitably generatea withdrawal syndrome as the body seeks to restore its“hedonic equilibrium.” Activation of corticotropin releas-ing factor (CRF)-containing neurons in the amygdala maymediate the negative emotional symptoms and also manyof the somatic symptoms that occur upon drug with-drawal [132]. Given that the dopaminergic drugs usedto treat PD share some of the psychomotor-activatingproperties of stimulant drugs such as amphetamines andcocaine [133,134], it is possible to speculate that recruit-ment of brain anti-reward systems, as an opponent pro-cess to excessive reward system activation by dopaminer-gic drugs, may be responsible for many of the symptoms




seen in PD patients as dopaminergic medication effectwears off. Resolution of intractable “off” period pain dur-ing dopaminergic “drug holidays” (see below) is consis-tent with this theory [3,41,42,135,136]. Further, distressingchronic pain alone has been reported to powerfully moti-vate the compulsive self-administration of dopaminergicdrugs in a PD patient [137].

Genetic factorsRecent animal and human studies suggest that geneticfactors are linked to individual differences in pain expe-rience. For example, polymorphisms in the gene forcatechol-O-methyltransferase (COMT), an enzyme thatdelays the breakdown of dopamine, influence sensitiv-ity to experimental pain, the risk of developing temporo-mandibular joint disorder (a common chronic pain con-dition), and also the clinical efficacy of opioid treatment[56,138,139]. In another study, a “pain-protective” haplo-type of the gene for GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis(an essential cofactor for catecholamine, serotonin, andnitric oxide production), was associated with less pain fol-lowing discectomy for persistent radicular low back pain,and reduced experimental pain sensitivity [140]. Geneticfactors have not been studied in relation to PD-relatedpain.

Diagnosis and management

Proper recognitionSome reports have highlighted the problem of delayeddiagnosis of PD (and sometimes inappropriate or inva-sive investigations and treatments) when patients presentfirst with pain. Greater awareness of this possibilityamong physicians (general practitioners, geriatricians,neurologists, orthopedists, and rheumatologists) shouldfacilitate earlier diagnosis and appropriate management[7,141,142]. In particular, patients presenting with frozenshoulder with no obvious precipitating factors should beassessed for signs of early parkinsonism, such as bradyki-nesia [22].

In evaluating pain complaints where PD has alreadybeen diagnosed, one of the physician’s first tasks is todetermine whether the pain syndrome represents a condi-tion requiring further investigations or specific treatment(e.g., myelopathy, focal neuropathy). In some cases, it maybe appropriate to seek specialty consultation (rheuma-tologic, orthopedic, vascular, etc.) [4]. One of the diffi-culties in diagnosing PD-related pain is the lack of spe-cific clinical features or diagnostic tests; the diagnosisoften is inferred by excluding other causes. No univer-sally accepted clinical diagnostic criteria for neuropathicpain exist [48,49] and, unlike most causes of neuropathicpain which typically exhibit both negative [46] and pos-

itive sensory phenomena in the same area innervatedby damaged nervous system pathways [143], the bed-side sensory examination in patients with central parkin-sonian pain typically does not reveal sensory deficits[2,3,12,24,35,50,61,91]. In one series, most cases of painconsidered to be “directly related” to PD were reportedas “vague painful sensations” that did not correspond towell-defined syndromes [2]. Just as in patients exhibitinga complicated motor response to l-dopa, an l-dopa chal-lenge test can sometimes help to clarify the relationshipof the sensory complaint to the patient’s medication cycle(e.g., documenting that pain occurs mainly as an end-of-dose or “off” phenomenon).

Even with proper recognition, management of PD-related pain is often challenging. This is similar to the sit-uation with chronic neuropathic pain in general, wherethe response to treatments is often inadequate [144] –this may reflect the existence of different neuronal painmechanisms in an individual patient [145]. Neverthe-less, the management goal should be to provide reliefand comfort so that patients experience the best possi-ble quality-of-life in spite of the disease. The treatment ofpain is important not only for relief of discomfort, but alsobecause pain may further exacerbate the reduced mobil-ity of PD patients [7,8] and other co-morbidities suchas depression and anxiety. Studies indicate that pain isundertreated in PD patients [2,19,23,146], and this maybe particularly true for PD-related pain [2]. One authorfound that one-fifth of PD patients reporting moderateto severe constant pain or pain dominating their daywere on no analgesics. Many patients with PD are elderlyand many are cognitively impaired; in non-PD popula-tions, these factors are associated with insufficient treat-ment of pain [36,147], possibly due to perceived risks ofpharmacotherapy [17]. Nevertheless, one study of non-demented subjects showed lower analgesic consumptionamong patients with PD-related pain compared with non-PD subjects, despite greater pain intensity and impact onquality-of-life [2].

Patient education and supportPhysicians should bear in mind that psychosocial factorsare a major component of the experience of chronic pain[143]. Patient education and support are critical compo-nents of successful management, including careful expla-nation of the cause of pain and the treatment plan. Studiesin patients with PD or pain have shown that expectationof treatment outcome is important to the production ofoptimum therapeutic effects (attributable, at least in part,to a “placebo” effect); this in turn is strongly influencedby the doctor–patient interaction [148]. Notably, one largestudy found that many PD patients experiencing painperceived that their general practitioners did not under-stand what it is like to live with the disease [25].



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Treatment of co-morbiditiesParticular attention should be paid to identifying coexist-ing co-morbidities such as depression, anxiety, and sleepdisturbances, which may act synergistically to increasedisability [2,143,149]. One study showed that depressionaccounted for most of the variance in pain severity [31].Anti-depressant medication may be indicated and selec-tive serotonin reuptake inhibitors (SSRIs), which have afavorable side effect profile, are typically first choice inPD patients [150] and may also alleviate anxiety [151]. Tri-cyclic anti-depressants may be useful for treating depres-sion in patients with chronic pain [6] and may alsoimprove disturbed sleep [143]. Low-dose quetiapine canbe helpful for insomnia [152].

Patients exhibiting prominent dysphoric “off” symp-toms (including pain, depression, anxiety, panic attacks,chest pressure, palpitations, tachypnea, and profusesweating), apparently disproportionate to the degreeof “off” state motor dysfunction, should be carefullyscreened for the dopamine dysregulation syndrome(DDS). The treatment of DDS has been reviewed else-where [133,153]. In general, rescue l-dopa or injections ofapomorphine should be avoided in patients thought to besusceptible to addiction.

Non-pharmacologic approaches to treat painMany patients manage pain by physical means, for exam-ple, massage, stretching, exercise, heat, or cold packs [19].In cases where pain appears to be related to posturalor other biomechanical abnormalities, rehabilitation mayhave a role [154]; for example, physical therapy may ame-liorate back pain and increase autonomy in these patients.In one study of PD patients with camptocormia, wearinga corset was effective in reducing back pain and was welltolerated [117]. The use of complementary medicine ther-apies is common in patients with PD [155], but their rolein symptom management remains unproven. Acupunc-ture may have a role in the treatment of some pain syn-dromes [156], but the evidence for this in PD is limited atpresent [157,158].

Pharmacologic approaches to treating pain –effective management of PDPain may be dramatically improved by effective treat-ment of parkinsonian motor symptoms [3]. Many patientsreport an improvement in pain when anti-parkinsoniantherapy is initiated [3,8,22], a classic example beingfrozen shoulder [22]. Pain that fluctuates in parallel withmotor fluctuations can be managed by modifying anti-parkinsonian therapy [3,20]. In cases where pain is asso-ciated with the “off” medication state, maximizing “on”time may help [20,159]. Strategies include an increase inthe dose or frequency of l-dopa or addition of controlled-release l-dopa, a COMT inhibitor, or a longer-acting agent

such as a dopamine agonist or MAO-B inhibitor. Apo-morphine rescue injections may be dramatically effectivein aborting severe “off” period pain within a few min-utes [136,160]. Although, to our knowledge, the effecton pain of continuous subcutaneous apomorphine infu-sion or enteral (intraduodenal) infusion of l-dopa has notbeen specifically studied, these treatments typically resultin substantial improvements in motor response fluctua-tions and dyskinesia [161,162]. Camptocormia is usuallynot greatly modified by PD medications [117], althoughsome authors have reported on axial dystonia (occur-ring as an end-of-dose or “off” phenomenon) respond-ing to increased l-dopa dose [163,164]. Pain aggravatedby choreiform dyskinesia (which typically occurs as apeak-dose phenomenon) may be ameliorated by usinganti-dyskinesia treatments (reduction of l-dopa, or useof amantadine, infusional therapies, or functional neu-rosurgery) [3]. Nevertheless, there remains a majority ofpatients in whom initiation or modification of dopamin-ergic therapy does not alleviate pain.

Transient l-dopa withdrawal (“drug holiday”) has beenreported to result in resolution of severe fluctuating dys-tonic [41,42,135] and non-dystonic [3,136] pain. For exam-ple, Quinn et al. described a patient who had severe“off” period abdominal and bilateral non-dystonic legpain who was much happier remaining off l-dopa per-manently (and being severely immobile as a result), butpain free [3]. However, this practice has been mostly rele-gated to the past because of the potential for precipitatingserious events such as a neuroleptic-like malignant syn-drome [165], and also limited efficacy – pain (like severemotor fluctuations) may reappear within a few days oftreatment reinitiation [3].

Analgesic agentsThere are very few clinical trial data concerning anal-gesic medication choice for PD-related pain that doesnot respond to optimization of anti-parkinsonian treat-ment. Guidance is available mainly from studies of othercauses of neuropathic pain, although it is possible thatdifferent types of neuropathic pain respond differentlyto treatments [144]. Individual variation in response tomedications used to treat neuropathic pain is substan-tial and unpredictable [144], and combination treatmentis often required because of the limited efficacy of singleagents [51]. Readers are referred to papers by Dworkinand colleagues for further details about management ofneuropathic pain in general [143,144]. The treatment ofsomatic or nociceptive pain should proceed along theusual lines and has also been reviewed elsewhere [166].The highly favorable risk/benefit ratio of acetaminophen(paracetamol) justifies a role for this agent as a near-routine background analgesic, notwithstanding the typeof pain involved [166].




First-line agents for neuropathic painTo our knowledge, there have been only two publishedclinical trials of treatment for PD-related pain (usingduloxetine and clozapine) [167,168]. In an open-labelstudy of duloxetine [a serotonin–norepinephrine reup-take inhibitor (SNRI)], non-depressed PD patients withpain of suspected central origin that did not respond tooptimization of anti-parkinsonian treatment responded tothis agent at doses of 30–60 mg daily [167]. However, thewell-known strong placebo effect in PD patients meansthat controlled studies are required [169]. Venlafaxine isalso efficacious for neuropathic pain in non-PD patientpopulations [166]. In addition to SNRIs, other recom-mended first-line treatments for neuropathic pain includetricyclic anti-depressants (TCAs) [29] and calcium chan-nel α2-δ ligands (gabapentin or pregabalin). Gabapentinand pregabalin have good tolerability and may improvesleep [144] and restless legs symptoms [170–172]. More-over, gabapentin has been reported to improve parkin-sonism [173–175], although there is a case report of thisagent inducing dyskinesia in PD [176].

Second-line agents (144)Opioids also have demonstrated efficacy in neuropathicpain [143], and there are case reports of efficacy in PD-related pain [10]. However, meperidine (pethidine) caninduce parkinsonism in neurologically normal subjects[177,178]. Morphine is probably less likely than meperi-dine to worsen parkinsonism in PD patients [40]. Thereis a potential for precipitating confusion or hallucina-tions [11], and constipation, a very common symptomin PD [179], usually requires concurrent management.Tramadol, an SNRI with a major metabolite that is aμ-opioid agonist [143]. was reported in one PD patient toimprove dramatically chronic diffuse burning pain andmajor depression that fluctuated in relation to l-dopadosing [137]. The risk of addiction to these agents isthought to be low in neuropathic pain patients withouta history of substance abuse, and we are not aware ofany reports of opioid addiction in PD patients. How-ever, “poly-substance” abuse in the context of dopamineagonist treatment and behavioral addictions has beenreported rarely [180]. Besides treatment with direct-actingdopamine agonists, red flags that may aid in identifyingpatients at higher risk for addictions include male gender,a personal or family history of substance dependence orimpulse control disorders, younger age at PD onset, andearly emergence of dyskinesia [181,182].

Third-line medicationsThese include other anti-epileptic agents. Again, the sideeffect profile should be considered in treatment selection,such as the potential for valproate to induce parkinson-ism and cognitive impairment [183,184]. There is someevidence to support the use of cannabinoids for neuro-

pathic pain secondary to multiple sclerosis [185]. One con-cern is the potential for these agents to precipitate psy-chosis [186], a common problem in the more advancedstages of PD. In a small, open-label study, clozapineimproved severe “cramp-like” parkinsonian pain unre-sponsive to manipulations of anti-parkinsonian therapyby ≥60% [168]. Clozapine has also been reported to allevi-ate oral and genital pain in PD [29]. A major disadvantageof using this agent is the requirement for long-term bloodmonitoring.

Pain clinic managementFor patients who have not responded adequately to phar-macologic management or those who have pain that isassociated with a high level of disability or distress, con-sultation with a pain specialist or referral to a multidisci-plinary pain management center may be helpful.

Treatments for dystoniaAgents that have been used successfully to treat parkin-sonian dystonia include amantadine [187], clonazepam[188], baclofen [43,189], anti-cholinergics [135], lithium[3], clozapine [168,190], and gabapentin [174]. Pacchettiet al. described complete the disappearance of painfulfoot dystonia in 70% of patients treated with botulinumtoxin injections into the affected muscles [113]. In anotherseries, seven of 10 PD patients with dystonic clenched fistexperienced pain relief with this treatment [191]. Camp-tocormia caused by rectus abdominis contraction can alsosometimes be ameliorated by botulinum toxin injections[117,192]. More invasive approaches to treat pain may beconsidered when simpler methods fail.

Electroconvulsive therapy (ECT)Snider et al. reported on a PD patient with severemedication-resistant truncal burning and depression whoimproved dramatically with ECT; otherwise, reports arelacking in PD [24]. ECT is an accepted treatment fortreatment-resistant PD depression and may also improvepsychosis and parkinsonism [193–195]. There are casereports of successful treatment of a variety of chronic painsyndromes in non-PD patients using ECT [196–199]. Someauthors found that ECT has analgesic properties indepen-dent of its effect on improving depression [197,198].

Rheumatologic/orthopedic proceduresIn patients with true rheumatologic disorders, proceduressuch as steroid injections and joint surgery (e.g., kneeor hip replacement for severe osteoarthritis) can relievepain and/or improve function [200–202]. For example,one study reported that 93% (62/67) of patients had no oronly slight pain after hip joint replacement after a follow-up of at least 2 years [201]. However, there may be higherrates of complications including immobilization-related



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lower limb dystonia/contracture [202,203] and infections(urinary tract infections, pneumonia) [201], and somestudies have reported longer hospitalizations [204] andpossibly higher mortality in operated PD patients [201].Anti-parkinsonian medications should be resumed with-out delay postoperatively, and this will also facilitatephysical therapy.

Functional neurosurgeryDeep brain stimulation (DBS) surgery has become anestablished treatment for advanced PD [205], with mul-tiple studies providing compelling evidence for a long-term effect on motor symptoms [206–208]. The majorityof studies suggest that subthalamic nucleus (STN) DBS issuperior to globus pallidus internus (GPi) DBS in improv-ing the cardinal motor features of PD [209], and bilateralSTN DBS has become the procedure of choice at mostcenters. Severe fluctuations in motor response to l-doparemain the primary indication for treating PD patientswith DBS, but important changes in non-motor symp-toms (including pain) are also seen postoperatively. In onestudy selecting PD patients with severe dystonia, STNDBS reduced “off” period dystonia and related pain by90 and 66%, respectively, at 6 months post-surgery [210].Loher et al. reported comparable improvements in “off”period dystonia and pain with GPi DBS [211]. The benefitof DBS on these symptoms appeared very early (immedi-ately, or within several days). Loher et al. concluded thatdisabling “off” period dystonia alone may be considereda good indication for functional neurosurgery.

Witjas et al. reported striking improvements in a rangeof non-motor fluctuations at 1 year post-STN DBS. Thegreatest reductions were in pain and sensory fluctuations(improvement reported by 84% of patients) (note thatthe analysis excluded “off” period dystonic pain) [212].Whether the improvement in non-motor fluctuationsrelates to a direct effect of stable (i.e., non-fluctuating)STN inhibition or to a process of striatal desensitizationdue to reduced l-dopa intake [121,213,214], or both, iscurrently not known. Nevertheless, complete eliminationof medication post-STN DBS clearly is not necessary formarked alleviation of dyskinesia or motor and non-motorfluctuations [212–214].

Although in most surgical centers lesional surgeryhas largely been surpassed by DBS surgery (one majorreason for this is the relatively high risk of adverseoutcomes with bilateral lesions), in many parts of theworld scarce medical resources will dictate the practiceof lesional surgery as a viable alternative [215]. Unilat-eral pallidotomy can provide lasting motor benefit [216].In a prospective study, Honey et al. found a significantreduction in pain scores 6 weeks after unilateral palli-dotomy, with a beneficial (and bilateral) effect still seenat 1 year [112]. Improvement was seen in somatic pain(e.g., arthritis or tendonitis triggered by tremor or dysk-

inesia) and musculoskeletal pain. However, the benefi-cial effect on dystonic pain was sustained in only half ofthe patients at 1 year and dysesthesias did not improve(only two patients had this to begin with). In anotherstudy, de Bie et al. found that patients with pain result-ing from parkinsonism often reported relief of pain con-tralateral to the pallidotomy, but the improvement of sen-sory complaints did not achieve statistical significance;in this study, postoperative assessment was performeda median of 5 months after surgery [217]. Baron et al.reported improvement in pain and discomfort in 10 of 12patients at 6 months but not at 1 year post-surgery [218].

Chronic epidural motor cortexstimulation (MCS)MCS was first introduced to relieve refractory pain; expe-rience with a few hundred patients in open-label studiesindicates that 50–60% of patients with medically refrac-tory neuropathic pain may benefit from the procedure[219]. MCS has also been suggested as a possible newtreatment method for movement disorders, including PD[220]; this approach would be simpler and safer than DBSof the basal ganglia. Some authors have reported impres-sive reduction of painful dystonia after MCS [221];) how-ever, data regarding its efficacy in ameliorating parkinso-nian motor symptoms are conflicting, with recent studiesreporting no motor benefit [222,223].

Acknowledgments

Dr Shen-Yang Lim wishes to acknowledge the mentor-ing provided by senior colleagues in the pain field: DrMichael J. Farrell, Associate Professor Stephen J. Gibson,and Professor Robert D. Helme.

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parkinson's disease volume 10 (non-motor and non-dopaminergic features) || pain and paresthesia...

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