- Email: [email protected]
Pain perception in patients with Parkinson’s disease
Journal of Clinical Neuroscience 20 (2013) 663–666
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Pain perception in patients with Parkinson’s disease Tomasz Tykocki a,⇑, Anna Kornakiewicz b, Tomasz Mandat c, Paweł Nauman a a
Department of Neurosurgery, Institute of Psychiatry and Neurology, Poland First Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland c Department of Neurosurgery, Institute of Oncology, Warsaw, Poland b
a r t i c l e
i n f o
Article history: Received 9 December 2011 Accepted 19 May 2012
Keywords: Parkinson’s disease Pain Visual analogue scale
a b s t r a c t Abnormalities in pain perception are a part of the clinical picture in Parkinson’s disease (PD) and belong to the category of non-motor symptoms. Two groups of patients were included in this study: (i) an experimental group of 36 patients with PD who were eligible for subthalamic deep brain stimulation (the experimental group [EG]) and (ii) a control group (CG) of 34 patients with a space-occupying lesion who were admitted for a framed stereotactic biopsy. Stereotactic frame fixation was used in both groups as a nociceptive stimulus. All participants were assessed for pain perception with two kinds of visual analogue scales (VAS) (a non-color VAS [ncVAS] and a color VAS [cVAS]) immediately after the stimulus (EG – ncVAS 1 and cVAS 1; CG – ncVAS 3 and cVAS 3) and 24 hours later (EG – ncVAS 2 and cVAS 2; CG – ncVAS 4 and cVAS 4). The means for the two pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for patients in the EG, while the mean ncVAS was 3, and the mean cVAS 3 was 6.1 for those in the CG. The pain intensity was significantly lower for patients with PD (EG) compared to those in the CG for both ncVAS and cVAS (p < 0.05 for each measure). The mean pain scores for ncVAS and cVAS measured 24 hours after the procedure were 3.18 and 2.79 for patients with PD (EG) and 6.10 and 5.77 for those in the CG, respectively. Pain intensity measured 24 hours after the procedure was significantly lower in those with PD (EG) compared to the CG. This study has demonstrated that pain perception in patients with PD is significantly lower than pain perception in non-parkinsonian patients. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Non-motor symptoms (NMS) of Parkinson’s disease (PD) are an integral part of the clinical symptomatology in both the premotor and advanced phases of the disease.1 The spectrum of NMS includes a variety of manifestations including dysautonomia, sleep disorders, sensory disturbances, fatigue, neuro-ophthalmological and neuropsychiatric symptoms,2 which significantly impair quality of life and increase the risk of mortality.3 NMS may precede the onset of cardinal motor symptoms and can be used as a screening tool, allowing for early diagnosis and early disease-modifying interventions.4 Recognition of NMS is crucial, not only for ascertaining the functional status of patients, but also for better understanding the nature of the neurodegenerative process in PD.5 Disturbance of pain perception corresponding to abnormalities in processing sensory input through the basal ganglia is part of the clinical picture.6 Alteration in pain perception has been shown to be disabling in approximately 50% of patients with PD.7 Several recent studies on pain perception in PD have demonstrated a decrease in the pain threshold and a lower tolerance of ⇑ Corresponding author. Tel.: +48 509 764 635. E-mail address: [email protected] (T. Tykocki). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.05.043
pain.8,9 However, Nolano et al.10 have shown that patients with PD display a significant increase in tactile and thermal thresholds, a reduction in mechanical pain perception and loss of epidermal nerve fibers and Meissner corpuscles. These results indicate that a peripheral deafferentation also contributes to the sensory dysfunction in PD and may be crucial in its pathogenesis. The pain threshold in PD is modulated by the basal ganglia and dopaminergic transmission, which is enhanced after levodopa administration. This increases the nociceptive flexion reflex,11–13 an objective index of nociceptive threshold, which is significantly lower in patients with PD.14 As there is some controversy about the pain threshold and the precise mechanism underlying pain disturbances in PD, aspects of pain perception need further research. One question is how pain perception in patients with PD under a nociceptive stimulus, such as stereotactic frame fixation, compares to that of a non-PD population. Pain perception can be assessed by measuring subjective pain intensity with a visual analog scale (VAS) or by measuring the objective nociceptive flexion reflex (R III). Given that recent data show a 16% higher RIII sensitivity compared to the pain threshold in experimental pain studies,15 we have chosen the VAS to measure the pain threshold in our study.
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Another sensory deficit in PD is impaired color perception, especially contrast sensitivity, and impairment of line orientation judgment.16 Patients may also suffer from drug-induced visual illusions and hallucinations (VH), which often include color. Contrast discrimination, color perception and image recognition have been shown to be significantly more impaired in patients with PD with VH than in those without VH and compared to healthy controls.17,18 For this reason, we chose to utilize a color VAS (cVAS) as well as a non-color VAS (ncVAS) in patients with PD. The main aim of this study was to determine subjective pain intensity during a stereotactic frame fixation procedure in patients with PD (the experimental group [EG]) compared to non–parkinsonian patients (the control group [CG]). Based on previous research, two hypotheses were proposed: (i) that the pain severity during a stereotactic frame fixation is different in patients with PD compared to a CG; and (ii) that assessment of pain perception using ncVAS differs from cVAS in the PD cohort but not in non-PD CG.
with PD underwent withdrawal of anti-parkinsonian drugs 24 hours before the procedure. Frame fixation was performed in a seated position in a preparation room by a neurosurgeon with a nurse assisting. Non-steroidal anti-inflammatory drugs were administered intravenously 20–30 minutes prior to frame fixation and local anesthesia with 1% lignocaine was injected subcutaneously and periosteal immediately before starting. The procedure was the same for both groups. Five minutes after frame fixation the first measurement was performed. Patients were assessed with both ncVAS and cVAS with 1 minute to 5 minutes break between measurements (ncVAS 1 and cVAS 1 for patients in the EG; ncVAS 3 and cVAS 3 for the CG). The second assessment was repeated 24 hours after the first (ncVAS 2 and cVAS 2 for the EG; ncVAS 4 and cVAS 4 for the CG). The scores for cVAS ranged from 0 to 10, with 0 indicating no pain and 10 indicating maximal pain, and there was also a continuous color spectrum scale ranging from blue (no pain) to red (maximum pain). The ncVAS used only the numeric scoring system.
2. Material and methods 2.3. Statistical analysis
2.1. Study participants Two groups of patients were included in the study. The EG included 36 patients with PD with a mean age of 54.3 years (± standard deviation [SD] of 4.5 years); the mean duration of PD was 9.29 ± 1.1 years. The CG comprised 34 patients with intracranial supratentorial brain tumors who were eligible for a stereotactic frame biopsy (mean age 51.1 ± 9.2 years). Patients with PD were categorized as stage 2 or stage 3 according to the Hoehn and Yahr Scale and were eligible for bilateral subthalamic deep brain stimulation (DBS) in accordance with the Core Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease (CAPSIT– PD) criteria.19 All patients with PD were taking anti-parkinsonian dopaminergic drugs (levodopa and/or dopamine agonists) and none suffered from acute or chronic pain related to PD (according to Ford’s classification),20 or from any other disease. Characteristics of both groups are presented in Table 1. The Beck Depression Inventory (BDI) and the Mini–Mental State Examination were used to measure mood and cognitive function. Patients were recruited from various neurology departments in Poland and referred to the Department of Neurosurgery at the Institute of Psychiatry and Neurology, Warsaw, Poland. The protocol was approved by the local ethics committee and all subjects gave written informed consent prior to the study. 2.2. Experimental protocol The stereotactic frame system (Leksell, Elekta, Stockholm, Sweden) was used for subthalamic nucleus DBS in patients with PD and for stereotactic frame biopsy in the control group. Patients
Table 1 Characteristics of patients with and without Parkinson’s disease (PD)
N Male (n) Age (years) PD duration (years) BDI UPDRS-III OFF LDD (mg) MMSE
Patients with PD (EG)
Control group (CG)
36 17 54.3 ± 4.5 9.29 ± 1.1 14.9 ± 10.8 53.4 ± 17.2 1188.4 ± 396.1 22.1 ± 3.8
34 19 51.1 ± 9.2 0 11.2±8.6 0 0 23.8 ± 5.1
All data are presented as mean ± standard deviation. BDI = Beck Depression Inventory, EG = expermental group, LDD = levodopa daily dose, MMSE = Mini–mental state examination, OFF = off medication state, PD = Parkinson’s disease, UPDRS = Unified Parkinson’s Disease Rating Scale.
Unpaired two-sample t-tests were used to assess mean differences between the PD group and the CG and paired t-tests were used to compare repeated measurements within each group. Linear correlation was used to correlate pain scores with age and disease duration. Statistical tests were considered significant at p < 0.05. Summary measures were expressed as mean ± SD. 3. Results The pain scores are presented in Table 2. The mean pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for the EG and 6.57 (ncVAS 3) and 6.1 (cVAS 3) for the CG. The pain intensity scores were significantly lower in the PD group compared to the control group (ncVAS 1 compared to ncVAS 3, p < 0.05); cVAS 1 compared to cVAS 3, p < 0.05). The mean pain intensity scores measured 24 hours after the procedure for ncVAS and cVAS, respectively, were 3.18 and 2.79 in the EG and 6.10 and 5.77 in the CG. The mean differences between groups for the 24-hour measurements were also statistically significant (ncVAS 2 compared to ncVAS 4, p < 0.05; cVAS 2 compared to cVAS 4, p < 0.05). However, the scores in each group decreased significantly over the 24-hour period when assessed with ncVAS (ncVAS 1 compared to ncVAS 2, p < 0.03; ncVAS 3 compared to ncVAS 4, p < 0.01), but not with cVAS (cVAS 1 compared to cVAS 2, p = 0.166; cVAS 3 compared to cVAS 4, p = 0.258). In both groups and at both times cVAS scores were lower than ncVAS, but the mean difference was statistically significant only in the EG assessed directly after frame fixation (mean difference = 0.53, p = 0.02) (Table 2).
Table 2 Visual analogue scale pain scores for patients with and without Parkinson’s disease (PD) Group
Assessment
Mean
SD
PD (EG)
ncVAS 1 cVAS 1 24 h ncVAS 2 24 h cVAS 2 ncVAS 3 cVAS 3 24 h ncVAS 4 24 h cVAS 4
3.59 3.06 3.18 2.79 6.57 6.10 6.10 5.77
1.02 0.71 0.83 0.66 1.15 1.20 0.87 0.75
Control group (CG)
cVAS = color visual analogue scale, EG = experimental group, ncVAS = non-color visual analogue scale, SD = standard deviation.
T. Tykocki et al. / Journal of Clinical Neuroscience 20 (2013) 663–666
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Fig. 1. A comparison of pain scores in males and females showing that in both groups the pain scores were not significantly different between males and females. CG = control group, cVAS = color visual analogue scale, EG = experimental group, ncVAS = non-color visual analogue scale.
Mean (SD) scores for the BDI were 14.9 ± 10.8 in patients with PD and 11.2 ± 8.6 in control patients, bur the difference between means was not statistically significant. Pain scores, measured by either cVAS or ncVAS, were not significantly correlated with age or duration of PD (p > 0.05). Pain scores were not significantly different between males and females, although there was a tendency for lower pain perception in male patients in both groups (Fig. 1). 4. Discussion The main finding of this study was a lower pain perception in the EG (patients with PD) compared to those in the CG (nonparkinsonian patients). The mean pain scores for both ncVAS and cVAS were almost 50% lower in patients with PD than in the control patients both immediately after and 24 hours after the pain stimulus. These results are not consistent with several recent studies showing an increased pain sensitivity in patients with PD. Mylius et al.8 reported a comparison of pain sensitivity between patients with PD and healthy elderly subjects showing lower scores for both the electrical pain threshold and the R III threshold in patients with PD. Another conclusion from this study was that duration and severity of PD symptoms increased pain sensitivity. Similar findings were reported from another study where the pain threshold and pain tolerance in both the hands and feet were significantly lower in patients with PD than in normal controls, but both groups had similar tactile discrimination thresholds to electrical stimuli. Interestingly, both groups showed lower sensory thresholds in hands than in feet.9 However, some studies report converse findings with a higher pain threshold in PD. Quantitative sensory testing showed a significant decreased perception of tactile and thermal stimuli and a significant reduction in mechanical pain perception in patients with PD compared to controls.11–13 A correlation between disease severity and increased mechanical pain perception has also been reported.10 Pain threshold assessed with flexion nociceptive reflex has also been found to be higher in patients with PD than in a control group of the same age.12 In one study pain perception in patients with unilateral PD, either with or without pain prior to PD diagnosis, has been compared.21 Subjective pain was evaluated using the VAS with von Frey filaments for tactile thresholds and contact thermodes for warm sensation (WS) and heat pain thresholds (HPT). Results showed that with respect to tactile and WS thresholds there were no differences between patients with or without pain or the control group, nor between sides. However, HPT was lower in patients
with PD who experienced pain compared to those who did not, and those who experienced pain in the more affected side.21 Functional MRI studies show dysfunction of the right prefrontal areas in PD, which are responsible for controlling attention through differentiating relevant from irrelevant visual stimuli.22 Our results provide further evidence of hypoalgesia in PD. One previous study indicated that this may be caused by peripheral deafferentation and dysfunction of afferent nociceptive fibers.10 Different mechanisms underlie pain perception in PD, with a crucial role played by the basal ganglia combined with the effect of dopaminergic dysfunction on objective pain perception. However both central and peripheral aspects of pain perception determine pain tolerance, and this may explain why pain threshold can be lower or higher in different studies. This study has shown that the stereotactic frame fixation procedure in patients with PD is not likely to trigger more pain than in non-parkinsonian patients, in fact it is perceived as less painful. This is of clinical importance as sterotactic frame fixation elicits nociceptive pain sensation and regardless of specificity or the level of impairment in pain pathways in PD, pain perception was lower than in the CG. Here it should be noted that the CG included patients with a space-occupied lesion, which may affect pain perception, and as such our results pertain to non-parkinsonian patients but not healthy people. These results do not shed light on how abnormalities in color perception correlate with deficits in pain perception, as there were no significant differences between measurements using color and non-color scales. However it is a very interesting research question as to how deficits in pain and color perception affect each other and this needs to be tested with a larger group of patients and different methodology. Of note is the higher pain score in ncVAS for both groups immediately after frame fixation compared to the score 24 hours after the procedure. This may reflect lower stimulus, endogenous analgesia, or possibly less affective component at the time of the initial pain experience. Although not statistically significant, the tendency for male subjects to perceive the procedure as less painful was an interesting finding. Neuromodulative treatment of PD with DBS has been proven to be effective in the management of various types of pain. In a 24-month follow-up study on the effects of subthalamic nucleus stimulation on PD-related pain, dystonic pain was reported as the most responsive (100%) to DBS, followed by central (54%), musculoskeletal (27%), and neuropathic radicular pain (17%).23 In another study the mean VAS score at 12 months was 80% lower, with the best response for dystonia and musculoskeletal pain.24 However, there are no studies reporting the effect of DBS on the perception of nociceptive pain.
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In summary, this study has shown that patients with PD display significantly lower pain perception under nociceptive stimuli. This indicates that stereotactic frame fixation procedures are not likely to be more painful in patients with PD compared to nonparkinsonian patients despite the general pain threshold changes associated with PD. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References 1. Chaudhuri KR, Healy DG, Schapira AH. National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5:235–45. 2. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368–76. 3. Mehndiratta M, Garg RK, Pandey S. Nonmotor symptom complex of Parkinson’s disease–an under-recognized entity. J Assoc Physicians India 2011;59:302–8. 4. Zesiewicz TA, Sullivan KL, Hauser RA. Nonmotor symptoms of Parkinson’s disease. Expert Rev Neurother 2006;6:1811–22. 5. Simuni T, Sethi K. Nonmotor manifestations of Parkinson’s disease. Ann Neurol 2008;64:S65–80. 6. Chudler EH, Dong WK. The role of the basal ganglia in nociception and pain. Pain 1995;60:3–38. 7. Goetz CG, Tanner CM, Levy M, et al. Pain in Parkinson’s disease. Mov Disord 1986;1:45–9. 8. Mylius V, Brebbermann J, Dohmann H, et al. Pain sensitivity and clinical progression in Parkinson’s disease. Mov Disord 2011;26:2220–5. 9. Zambito Marsala S, Tinazzi M, Vitaliani R, et al. Spontaneous pain, pain threshold, and pain tolerance in Parkinson’s disease. J Neurol 2011;258:627–33.
10. Nolano M, Provitera V, Estraneo A, et al. Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain 2008;131:1903–11. 11. Massetani R, Lucchetti R, Vignocchi G, et al. Pain threshold and polysynaptic components of the blink reflex in Parkinson’s disease. Funct Neurol 1989;4:199–202. 12. Guieu R, Pouget J, Serratrice G. Nociceptive threshold and Parkinson disease. Rev Neurol (Paris) 1992;148:641–4. 13. Urakami K, Takahashi K, Matsushima E, et al. The threshold of pain and neurotransmitter’s change on pain in Parkinson’s disease. Jpn J Psychiatry Neurol 1990;44:589–93. 14. Gerdelat-Mas A, Simonetta-Moreau M, Thalamas C, et al. Levodopa raises objective pain threshold in Parkinson’s disease: a RIII reflex study. J Neurol Neurosurg Psychiatry 2007;78:1140–2. 15. Micalos PS, Drinkwater EJ, Cannon J, et al. Reliability of the nociceptive flexor reflex (RIII) threshold and association with Pain threshold. Eur J Appl Physiol 2009;105:55–62. 16. Uc EY, Rizzo M, Anderson SW, et al. Visual dysfunction in Parkinson disease without dementia. Neurology 2005;65:1907–13. 17. Pandya M, Kubu CS, Giroux ML. Parkinson disease: not just a movement disorder. Cleve Clin J Med 2008;75:856–64. 18. Meppelink AM, Koerts J, Borg M, et al. Visual object recognition and attention in Parkinson’s disease patients with visual hallucinations. Mov Disord 2008;23:1906–12. 19. Defer GL, Widner H, Marié RM, et al. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999 Jul;14:572–84. 20. Ford B. Pain in Parkinson’s disease. Clin Neurosci 1998;5:63–72. 21. Djaldetti R, Shifrin A, Rogowski Z, et al. Quantitative measurement of pain sensation in patients with Parkinson disease. Neurology 2004;62:2171–5. 22. Ramírez-Ruiz B, Martí MJ, Tolosa E, et al. Brain response to complex visual stimuli in Parkinson’s patients with hallucinations: a functional magnetic resonance imaging study. Mov Disorde 2008;23:2335–43. 23. Kim HJ, Jeon BS, Lee JY, et al. The benefit of subthalamic deep brain stimulation on pain in Parkinson disease: a 2-year follow-upstudy. Neurosurgery 2012;70:18–23. 24. Oshima H, Katayama Y, Morishita T, et al. Subthalamic nucleus stimulation for attenuation of pain related to Parkinson disease. J Neurosurg 2012;116:99–106.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Pain perception in patients with Parkinson’s disease Tomasz Tykocki a,⇑, Anna Kornakiewicz b, Tomasz Mandat c, Paweł Nauman a a
Department of Neurosurgery, Institute of Psychiatry and Neurology, Poland First Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland c Department of Neurosurgery, Institute of Oncology, Warsaw, Poland b
a r t i c l e
i n f o
Article history: Received 9 December 2011 Accepted 19 May 2012
Keywords: Parkinson’s disease Pain Visual analogue scale
a b s t r a c t Abnormalities in pain perception are a part of the clinical picture in Parkinson’s disease (PD) and belong to the category of non-motor symptoms. Two groups of patients were included in this study: (i) an experimental group of 36 patients with PD who were eligible for subthalamic deep brain stimulation (the experimental group [EG]) and (ii) a control group (CG) of 34 patients with a space-occupying lesion who were admitted for a framed stereotactic biopsy. Stereotactic frame fixation was used in both groups as a nociceptive stimulus. All participants were assessed for pain perception with two kinds of visual analogue scales (VAS) (a non-color VAS [ncVAS] and a color VAS [cVAS]) immediately after the stimulus (EG – ncVAS 1 and cVAS 1; CG – ncVAS 3 and cVAS 3) and 24 hours later (EG – ncVAS 2 and cVAS 2; CG – ncVAS 4 and cVAS 4). The means for the two pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for patients in the EG, while the mean ncVAS was 3, and the mean cVAS 3 was 6.1 for those in the CG. The pain intensity was significantly lower for patients with PD (EG) compared to those in the CG for both ncVAS and cVAS (p < 0.05 for each measure). The mean pain scores for ncVAS and cVAS measured 24 hours after the procedure were 3.18 and 2.79 for patients with PD (EG) and 6.10 and 5.77 for those in the CG, respectively. Pain intensity measured 24 hours after the procedure was significantly lower in those with PD (EG) compared to the CG. This study has demonstrated that pain perception in patients with PD is significantly lower than pain perception in non-parkinsonian patients. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Non-motor symptoms (NMS) of Parkinson’s disease (PD) are an integral part of the clinical symptomatology in both the premotor and advanced phases of the disease.1 The spectrum of NMS includes a variety of manifestations including dysautonomia, sleep disorders, sensory disturbances, fatigue, neuro-ophthalmological and neuropsychiatric symptoms,2 which significantly impair quality of life and increase the risk of mortality.3 NMS may precede the onset of cardinal motor symptoms and can be used as a screening tool, allowing for early diagnosis and early disease-modifying interventions.4 Recognition of NMS is crucial, not only for ascertaining the functional status of patients, but also for better understanding the nature of the neurodegenerative process in PD.5 Disturbance of pain perception corresponding to abnormalities in processing sensory input through the basal ganglia is part of the clinical picture.6 Alteration in pain perception has been shown to be disabling in approximately 50% of patients with PD.7 Several recent studies on pain perception in PD have demonstrated a decrease in the pain threshold and a lower tolerance of ⇑ Corresponding author. Tel.: +48 509 764 635. E-mail address: [email protected] (T. Tykocki). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.05.043
pain.8,9 However, Nolano et al.10 have shown that patients with PD display a significant increase in tactile and thermal thresholds, a reduction in mechanical pain perception and loss of epidermal nerve fibers and Meissner corpuscles. These results indicate that a peripheral deafferentation also contributes to the sensory dysfunction in PD and may be crucial in its pathogenesis. The pain threshold in PD is modulated by the basal ganglia and dopaminergic transmission, which is enhanced after levodopa administration. This increases the nociceptive flexion reflex,11–13 an objective index of nociceptive threshold, which is significantly lower in patients with PD.14 As there is some controversy about the pain threshold and the precise mechanism underlying pain disturbances in PD, aspects of pain perception need further research. One question is how pain perception in patients with PD under a nociceptive stimulus, such as stereotactic frame fixation, compares to that of a non-PD population. Pain perception can be assessed by measuring subjective pain intensity with a visual analog scale (VAS) or by measuring the objective nociceptive flexion reflex (R III). Given that recent data show a 16% higher RIII sensitivity compared to the pain threshold in experimental pain studies,15 we have chosen the VAS to measure the pain threshold in our study.
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Another sensory deficit in PD is impaired color perception, especially contrast sensitivity, and impairment of line orientation judgment.16 Patients may also suffer from drug-induced visual illusions and hallucinations (VH), which often include color. Contrast discrimination, color perception and image recognition have been shown to be significantly more impaired in patients with PD with VH than in those without VH and compared to healthy controls.17,18 For this reason, we chose to utilize a color VAS (cVAS) as well as a non-color VAS (ncVAS) in patients with PD. The main aim of this study was to determine subjective pain intensity during a stereotactic frame fixation procedure in patients with PD (the experimental group [EG]) compared to non–parkinsonian patients (the control group [CG]). Based on previous research, two hypotheses were proposed: (i) that the pain severity during a stereotactic frame fixation is different in patients with PD compared to a CG; and (ii) that assessment of pain perception using ncVAS differs from cVAS in the PD cohort but not in non-PD CG.
with PD underwent withdrawal of anti-parkinsonian drugs 24 hours before the procedure. Frame fixation was performed in a seated position in a preparation room by a neurosurgeon with a nurse assisting. Non-steroidal anti-inflammatory drugs were administered intravenously 20–30 minutes prior to frame fixation and local anesthesia with 1% lignocaine was injected subcutaneously and periosteal immediately before starting. The procedure was the same for both groups. Five minutes after frame fixation the first measurement was performed. Patients were assessed with both ncVAS and cVAS with 1 minute to 5 minutes break between measurements (ncVAS 1 and cVAS 1 for patients in the EG; ncVAS 3 and cVAS 3 for the CG). The second assessment was repeated 24 hours after the first (ncVAS 2 and cVAS 2 for the EG; ncVAS 4 and cVAS 4 for the CG). The scores for cVAS ranged from 0 to 10, with 0 indicating no pain and 10 indicating maximal pain, and there was also a continuous color spectrum scale ranging from blue (no pain) to red (maximum pain). The ncVAS used only the numeric scoring system.
2. Material and methods 2.3. Statistical analysis
2.1. Study participants Two groups of patients were included in the study. The EG included 36 patients with PD with a mean age of 54.3 years (± standard deviation [SD] of 4.5 years); the mean duration of PD was 9.29 ± 1.1 years. The CG comprised 34 patients with intracranial supratentorial brain tumors who were eligible for a stereotactic frame biopsy (mean age 51.1 ± 9.2 years). Patients with PD were categorized as stage 2 or stage 3 according to the Hoehn and Yahr Scale and were eligible for bilateral subthalamic deep brain stimulation (DBS) in accordance with the Core Assessment Program for Surgical Interventional Therapies in Parkinson’s Disease (CAPSIT– PD) criteria.19 All patients with PD were taking anti-parkinsonian dopaminergic drugs (levodopa and/or dopamine agonists) and none suffered from acute or chronic pain related to PD (according to Ford’s classification),20 or from any other disease. Characteristics of both groups are presented in Table 1. The Beck Depression Inventory (BDI) and the Mini–Mental State Examination were used to measure mood and cognitive function. Patients were recruited from various neurology departments in Poland and referred to the Department of Neurosurgery at the Institute of Psychiatry and Neurology, Warsaw, Poland. The protocol was approved by the local ethics committee and all subjects gave written informed consent prior to the study. 2.2. Experimental protocol The stereotactic frame system (Leksell, Elekta, Stockholm, Sweden) was used for subthalamic nucleus DBS in patients with PD and for stereotactic frame biopsy in the control group. Patients
Table 1 Characteristics of patients with and without Parkinson’s disease (PD)
N Male (n) Age (years) PD duration (years) BDI UPDRS-III OFF LDD (mg) MMSE
Patients with PD (EG)
Control group (CG)
36 17 54.3 ± 4.5 9.29 ± 1.1 14.9 ± 10.8 53.4 ± 17.2 1188.4 ± 396.1 22.1 ± 3.8
34 19 51.1 ± 9.2 0 11.2±8.6 0 0 23.8 ± 5.1
All data are presented as mean ± standard deviation. BDI = Beck Depression Inventory, EG = expermental group, LDD = levodopa daily dose, MMSE = Mini–mental state examination, OFF = off medication state, PD = Parkinson’s disease, UPDRS = Unified Parkinson’s Disease Rating Scale.
Unpaired two-sample t-tests were used to assess mean differences between the PD group and the CG and paired t-tests were used to compare repeated measurements within each group. Linear correlation was used to correlate pain scores with age and disease duration. Statistical tests were considered significant at p < 0.05. Summary measures were expressed as mean ± SD. 3. Results The pain scores are presented in Table 2. The mean pain scores assessed directly after frame fixation were 3.59 (ncVAS 1) and 3.06 (cVAS 1) for the EG and 6.57 (ncVAS 3) and 6.1 (cVAS 3) for the CG. The pain intensity scores were significantly lower in the PD group compared to the control group (ncVAS 1 compared to ncVAS 3, p < 0.05); cVAS 1 compared to cVAS 3, p < 0.05). The mean pain intensity scores measured 24 hours after the procedure for ncVAS and cVAS, respectively, were 3.18 and 2.79 in the EG and 6.10 and 5.77 in the CG. The mean differences between groups for the 24-hour measurements were also statistically significant (ncVAS 2 compared to ncVAS 4, p < 0.05; cVAS 2 compared to cVAS 4, p < 0.05). However, the scores in each group decreased significantly over the 24-hour period when assessed with ncVAS (ncVAS 1 compared to ncVAS 2, p < 0.03; ncVAS 3 compared to ncVAS 4, p < 0.01), but not with cVAS (cVAS 1 compared to cVAS 2, p = 0.166; cVAS 3 compared to cVAS 4, p = 0.258). In both groups and at both times cVAS scores were lower than ncVAS, but the mean difference was statistically significant only in the EG assessed directly after frame fixation (mean difference = 0.53, p = 0.02) (Table 2).
Table 2 Visual analogue scale pain scores for patients with and without Parkinson’s disease (PD) Group
Assessment
Mean
SD
PD (EG)
ncVAS 1 cVAS 1 24 h ncVAS 2 24 h cVAS 2 ncVAS 3 cVAS 3 24 h ncVAS 4 24 h cVAS 4
3.59 3.06 3.18 2.79 6.57 6.10 6.10 5.77
1.02 0.71 0.83 0.66 1.15 1.20 0.87 0.75
Control group (CG)
cVAS = color visual analogue scale, EG = experimental group, ncVAS = non-color visual analogue scale, SD = standard deviation.
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Fig. 1. A comparison of pain scores in males and females showing that in both groups the pain scores were not significantly different between males and females. CG = control group, cVAS = color visual analogue scale, EG = experimental group, ncVAS = non-color visual analogue scale.
Mean (SD) scores for the BDI were 14.9 ± 10.8 in patients with PD and 11.2 ± 8.6 in control patients, bur the difference between means was not statistically significant. Pain scores, measured by either cVAS or ncVAS, were not significantly correlated with age or duration of PD (p > 0.05). Pain scores were not significantly different between males and females, although there was a tendency for lower pain perception in male patients in both groups (Fig. 1). 4. Discussion The main finding of this study was a lower pain perception in the EG (patients with PD) compared to those in the CG (nonparkinsonian patients). The mean pain scores for both ncVAS and cVAS were almost 50% lower in patients with PD than in the control patients both immediately after and 24 hours after the pain stimulus. These results are not consistent with several recent studies showing an increased pain sensitivity in patients with PD. Mylius et al.8 reported a comparison of pain sensitivity between patients with PD and healthy elderly subjects showing lower scores for both the electrical pain threshold and the R III threshold in patients with PD. Another conclusion from this study was that duration and severity of PD symptoms increased pain sensitivity. Similar findings were reported from another study where the pain threshold and pain tolerance in both the hands and feet were significantly lower in patients with PD than in normal controls, but both groups had similar tactile discrimination thresholds to electrical stimuli. Interestingly, both groups showed lower sensory thresholds in hands than in feet.9 However, some studies report converse findings with a higher pain threshold in PD. Quantitative sensory testing showed a significant decreased perception of tactile and thermal stimuli and a significant reduction in mechanical pain perception in patients with PD compared to controls.11–13 A correlation between disease severity and increased mechanical pain perception has also been reported.10 Pain threshold assessed with flexion nociceptive reflex has also been found to be higher in patients with PD than in a control group of the same age.12 In one study pain perception in patients with unilateral PD, either with or without pain prior to PD diagnosis, has been compared.21 Subjective pain was evaluated using the VAS with von Frey filaments for tactile thresholds and contact thermodes for warm sensation (WS) and heat pain thresholds (HPT). Results showed that with respect to tactile and WS thresholds there were no differences between patients with or without pain or the control group, nor between sides. However, HPT was lower in patients
with PD who experienced pain compared to those who did not, and those who experienced pain in the more affected side.21 Functional MRI studies show dysfunction of the right prefrontal areas in PD, which are responsible for controlling attention through differentiating relevant from irrelevant visual stimuli.22 Our results provide further evidence of hypoalgesia in PD. One previous study indicated that this may be caused by peripheral deafferentation and dysfunction of afferent nociceptive fibers.10 Different mechanisms underlie pain perception in PD, with a crucial role played by the basal ganglia combined with the effect of dopaminergic dysfunction on objective pain perception. However both central and peripheral aspects of pain perception determine pain tolerance, and this may explain why pain threshold can be lower or higher in different studies. This study has shown that the stereotactic frame fixation procedure in patients with PD is not likely to trigger more pain than in non-parkinsonian patients, in fact it is perceived as less painful. This is of clinical importance as sterotactic frame fixation elicits nociceptive pain sensation and regardless of specificity or the level of impairment in pain pathways in PD, pain perception was lower than in the CG. Here it should be noted that the CG included patients with a space-occupied lesion, which may affect pain perception, and as such our results pertain to non-parkinsonian patients but not healthy people. These results do not shed light on how abnormalities in color perception correlate with deficits in pain perception, as there were no significant differences between measurements using color and non-color scales. However it is a very interesting research question as to how deficits in pain and color perception affect each other and this needs to be tested with a larger group of patients and different methodology. Of note is the higher pain score in ncVAS for both groups immediately after frame fixation compared to the score 24 hours after the procedure. This may reflect lower stimulus, endogenous analgesia, or possibly less affective component at the time of the initial pain experience. Although not statistically significant, the tendency for male subjects to perceive the procedure as less painful was an interesting finding. Neuromodulative treatment of PD with DBS has been proven to be effective in the management of various types of pain. In a 24-month follow-up study on the effects of subthalamic nucleus stimulation on PD-related pain, dystonic pain was reported as the most responsive (100%) to DBS, followed by central (54%), musculoskeletal (27%), and neuropathic radicular pain (17%).23 In another study the mean VAS score at 12 months was 80% lower, with the best response for dystonia and musculoskeletal pain.24 However, there are no studies reporting the effect of DBS on the perception of nociceptive pain.
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In summary, this study has shown that patients with PD display significantly lower pain perception under nociceptive stimuli. This indicates that stereotactic frame fixation procedures are not likely to be more painful in patients with PD compared to nonparkinsonian patients despite the general pain threshold changes associated with PD. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References 1. Chaudhuri KR, Healy DG, Schapira AH. National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5:235–45. 2. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368–76. 3. Mehndiratta M, Garg RK, Pandey S. Nonmotor symptom complex of Parkinson’s disease–an under-recognized entity. J Assoc Physicians India 2011;59:302–8. 4. Zesiewicz TA, Sullivan KL, Hauser RA. Nonmotor symptoms of Parkinson’s disease. Expert Rev Neurother 2006;6:1811–22. 5. Simuni T, Sethi K. Nonmotor manifestations of Parkinson’s disease. Ann Neurol 2008;64:S65–80. 6. Chudler EH, Dong WK. The role of the basal ganglia in nociception and pain. Pain 1995;60:3–38. 7. Goetz CG, Tanner CM, Levy M, et al. Pain in Parkinson’s disease. Mov Disord 1986;1:45–9. 8. Mylius V, Brebbermann J, Dohmann H, et al. Pain sensitivity and clinical progression in Parkinson’s disease. Mov Disord 2011;26:2220–5. 9. Zambito Marsala S, Tinazzi M, Vitaliani R, et al. Spontaneous pain, pain threshold, and pain tolerance in Parkinson’s disease. J Neurol 2011;258:627–33.
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