ORIGINAL ARTICLE
Widespread Pressure Pain Hypersensitivity in Patients With Multiple Sclerosis With and Without Pain as Sign of Central Sensitization Ce´sar Ferna´ndez-de-las-Pen˜as, PT, PhD, DMSc,*wz Ricardo Ortega-Santiago, PT, PhD,*w Rosa Ortı´z-Gutie´rrez, PT, PhD,y Ana B. Caminero, MD,8 Jaime Salom-Moreno, PT, PhD,*w and Lars Arendt-Nielsen, DMSc, PhDz
Objective: To determine the presence of widespread pressure hyperalgesia in multiple sclerosis (MS) patients with and without pain and its association with pain and fatigue. Methods: A total of 108 individuals with definite MS, 49 men and 59 women (mean age, 44 ± 8 y) and 108 age-matched and sexmatched pain-free controls (mean age, 44 ± 9 y) were included. Fifty patients (n = 58, 54%) reported pain and 50 (46%) did not. Pressure pain threshold (PPT) was bilaterally assessed over supraorbital, infraorbital, mental, median, radial and ulnar nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscle by an assessor blinded to the patient’s condition. The intensity of pain was assessed with a numerical pain rate scale (0 to 10), fatigue was determined with the Fatigue Impact Scale, and depression was evaluated with the Beck Depression Inventory. Results: The analyses of covariance revealed that PPT were significantly decreased bilaterally over the supraorbital, infraorbital, mental, median, ulnar and radial nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscles in patients with MS compared with pain-free controls (all, P < 0.001). No significant differences existed between MS patients with pain and those without pain (all P > 0.944). Patients with pain exhibited higher fatigue and depression than those patients without pain (P < 0.05). PPT was not associated with any clinical variable, that is, pain, depression, or fatigue. Conclusions: Our study found widespread pressure pain hyperalgesia in individuals with MS as compared with pain-free controls. No differences existed between MS patients with pain and those without pain in the presence of widespread pressure sensitivity. Current results suggest that MS is associated with sensory hyperexcitability of the central nervous system or dysfunction in endogenous pain modulatory systems. Key Words: multiple sclerosis, pressure pain threshold, sensitization, pain
(Clin J Pain 2015;31:66–72) Received for publication November 11, 2013; revised February 19, 2014; accepted January 28, 2014. From the *Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, Alcorco´n; yDepartment of Physical Therapy, Universidad Antonio de Nebrija; wLaboratory of Esthesiology, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorco´n, Madrid; 8Department of Neurology, Hospital Nuestra Sen˜ora de Sonsoles, Avila, Spain; and zDepartment of Health Science and Technology, Centre for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark. The authors declare no conflict of interest. Reprints: Ce´sar Ferna´ndez-de-las-Pen˜as, PT, PhD, DMSc, Laboratory of Esthesiology, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avenida de Atenas s/n, Alcorco´n 28922, Madrid, Spain (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins DOI: 10.1097/AJP.0000000000000084
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P
ain is a key symptom experienced by many individuals with multiple sclerosis (MS) and has started to receive increased attention in the recent years. Several patients with MS who experience pain describe it as one of the worst symptoms they had. The prevalence rate of pain in MS ranges from 29% to 82% depending on the country and the type of pain considered.1–4 A recent meta-analysis has pooled an overall pain prevalence of 63% (55% to 70%).5 As pain is associated to impaired quality of life and disability and represents an important therapeutic target in patients with MS, a better understanding of the mechanisms involved could contribute to the development of potential treatment strategies. Although the mechanisms underlying pain in MS have not yet been clarified, it has been linked to changes of the central pathways. Some theories explaining pain in MS suggest that injury of spinothalamic pathway results in a disinhibition of descending pain pathways or an imbalance between different inputs, and that structural lesions in the central nervous system cause a state of hyperexcitability (central sensitization) by increasing neuronal activity (spontaneous or evoked) at the site of injury and at remote sites.6 Central sensitization is usually assessed with quantitative sensory testing (eg, vibration, thermal, mechanical/ pressure, or electrical) being the assessment of pressure pain thresholds (PPTs) the most common way of assessing pain transmission, particularly in musculoskeletal chronic conditions.7 Some studies have investigated nociceptive processing in patients with MS and observed abnormalities in thermal pain thresholds.8–10 Leocani et al11 reported that patients with MS exhibited deficits in vibration thresholds as compared with healthy people and Svendsen et al12 showed that MS patients with pain exhibited lower PPTs and cold allodynia over the site of pain than patients without pain. A more recent study has confirmed that patients with MS and pain exhibit abnormal thermal detection thresholds.13 All these studies suggest the presence of abnormal nociceptive transmission in individuals with MS. However, these studies investigated quantitative sensory tests in one region and most of them investigated just thermal thresholds. To further confirm the presence of abnormal nociceptive transmission in MS, quantitative sensory tests should be investigated in several areas to investigate for widespread sensitization. It has been suggested that the presence of widespread pressure hyperalgesia over different tissues reflects a sign of abnormal pain processing.14 Several studies have observed the presence of widespread pressure pain hyperalgesia as a manifestation of abnormal nociceptive processing in musculoskeletal pain (eg, headache, fibromyalgia, Clin J Pain
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temporomandibular pain),15–18 neuropathic pain (eg, carpal tunnel syndrome),19 and neurological disorders (eg, Parkinson disease).20 The presence of widespread pressure pain hypersensitivity has been associated with poorer prognosis in individuals with chronic whiplash-associated disorders.21 There is no study investigating whether widespread pressure pain hypersensitivity over deep tissues is a feature of individuals with MS with pain and those without pain as manifestation of central sensitization process. The aim of our study was to investigate widespread pressure pain hyperalgesia in MS patients with and without pain and its association with clinical pain intensity and self-reported general fatigue.
METHODS Participants Consecutive individuals with definite MS according to the modified McDonald criteria and diagnosis by experienced neurologists were enrolled in the current study.22 Patients with MS with and without pain were included. Both neurogenic and non-neurogenic pain lasting for >3 months and of intensity >3 on a numerical pain rate scale (0 to 10) were considered. The exclusion criteria included other known neurological diseases, including herniated disk and other disorders of the spine, renal diseases, cancer, diabetes mellitus, severe psychiatric disease, and a Mini Mental State Examination score of 0.05). Differences in demographic and clinical variables among the groups were assessed with a 1-way analysis of variance (ANOVA). Demographic (age, sex, height, weight) and clinical variables (pain, fatigue) were entered as covariates in later analyses. Separated 3-way analyses of covariance (ANCOVA) were used to investigate the differences in PPT with point (C5-C6, second metacarpal, tibialis anterior, supraorbital, infraorbital, mental, median, and radial and ulnar nerves) and side (dominant, nondominant) as the within-subject factors and group (MS with pain, MS without pain, controls) as between-subjects factor. Post hoc comparisons were carried out with the Tukey test. The Pearson correlation test (r) was used to determine the association between PPTs and the clinical variables relating to pain symptoms and fatigue. The statistical analysis was conducted at a 95% confidence level and a P value 0.715). The post hoc analysis revealed that MS patients exhibited bilateral lower PPT than pain-free controls (all, P < 0.001), without differences between those with and without pain (all, P > 0.926) The inclusion of any
TABLE 1. Clinical and Demographic Characteristics of Patients With MS With and Without Pain and Healthy Controls
Demographic data Sex (M/F) Age (y) Height (cm) Weight (kg) Clinical data of patients with Disease duration (y) Disease course [n (%)] Relapsing remitting Secondary progressive Primary progressive EDDS (0-10) FIS (total score, 0-84) BDI-II (0-21)
MS With Pain (n = 58)
MS Without Pain (n = 50)
Pain-free Controls (n = 108)
P
29/29 44 ± 8 (41-46) 169.9 ± 9.6 (167.4-172.6) 72.2 ± 14.4 (67.7-76.6) MS 13.1 ± 8.4 (10.9-15.3)
20/30 45 ± 7 (43-47) 169.5 ± 9.1 (166.9-172.2) 70.3 ± 13.2 (66.5-74.2)
49/59 44 ± 8 (43-46) 168.7 ± 9.7 (166.8-170.6) 70.0 ± 13.1 (67.6-73.7)
w2 = 1.104; P = 0.576 F = 0.555; P = 0.575 F = 0.350; P = 0.705 F = 0.814; P = 0.444
12.4 ± 7.5 (10.3-14.6)
—
t = 0.477; P = 0.634
42 10 5 3.7 ± 1.8 43.6 ± 20.6 11.7 ± 6.9
38 9 3 3.4 ± 1.7 35.5 ± 18.8 9.3 ± 6.2
—
w2 = 3.008; P = 0.390
— — —
t = 0.937; P = 0.351 t = 2.130; P = 0.035 t = 2.005; P = 0.047
(73) (18) (9) (3.3-4.2) (37.7-49.5) (9.7-13.6)
(76) (18) (6) (2.9-3.9) (30.5-40.4) (7.7-11.0)
Data are expressed as means ± SD (95% confidence interval). BDI-I indicates Beck Depression Inventory; EDDS, Expanded Disability Status Scale; FIS, Fatigue Impact Scale; MS, multiple sclerosis.
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Widespread Pressure Hypersensitivity in Multiple Sclerosis
FIGURE 1. Areas of sensory pain symptoms in patients with multiple sclerosis.
clinical variable as covariate did not influence the results with exception of sex (all, P < 0.01): PPT were lower in female than in male in all the groups. Table 2 summarizes PPT assessed over the trigeminal nerve trunks and Table 3 shows PPT over upper extremity nerve trunks in both sides in the 3 groups.
Pressure Pain Sensitivity Over Non-Neural Tissues ANCOVA revealed significant differences between groups, but not between sides, for PPT over C5-C6 joint (group: F = 162.117; P < 0.001; side: F = 1.051; P = 0.306), second metacarpal (group: F = 129.028; P < 0.001; side: F = 0.099, P = 0.754), and tibialis anterior muscle (group: F = 187.806; P < 0.001; side: F = 0.027; P = r
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0.870). No significant side and group interaction was either found (all, P > 0.585). Post hoc analyses revealed that MS patients exhibited bilateral lower PPT than pain-free controls (all, P < 0.001), but without differences between those with and without pain (all, P > 0.944). The inclusion of any clinical variable as covariate did not influence the results, again with exception of sex (all, P < 0.01): PPTs were lower in female than in male in the 3 groups. Table 4 details PPT over C5-C6 zygapophyseal joints, second metacarpal, and tibialis anterior muscles in both the sides in all groups.
Clinical Features and Widespread Pressure Sensitivity in Patients With MS With Pain In MS patients with pain, the area of perceived pain was negatively associated with PPT over radial (dominant: www.clinicalpain.com |
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TABLE 2. Differences in Pressure Pain Thresholds (kPa) Over the Supraorbital, Infraorbital, and Mental Nerve Trunks Between Patients With Multiple Sclerosis With and Without Pain and Pain-free Controls
Supraorbital Nerve*
Infraorbital Nerve*
Mental Nerve*
183.5 ± 44.4 (172.1-194.9) 184.5 ± 50.2 (173.1-195.8)
197.8 ± 53.2 (185.4-210.2) 203.3 ± 51.1 (190.9-215.7)
(161.9-179.5) (156.6-175.1)
180.4 ± 43.2 (169.9-190.8) 186.9 ± 54.9 (176.3-197.4)
191.9 ± 48.9 (180.5-203.5) 195.1 ± 50.2 (183.5-206.6)
(263.4-276.3) (264.1-277.0)
286.1 ± 33.6 (278.4-293.9) 284.9 ± 29.4 (277.2-292.7)
296.0 ± 36.5 (287.6-304.5) 295.5 ± 38.4 (287.1-303.9)
Patients with multiple sclerosis with pain (n = 58) Dominant 175.5 ± 45.7 (166.0-184.9) Nondominant 174.1 ± 39.9 (164.5-183.6) Patients with multiple sclerosis without pain (n = 50) Dominant 170.7 ± 29.8 Nondominant 165.4 ± 28.6 Healthy controls (n = 108) Dominant 269.8 ± 31.3 Nondominant 270.6 ± 32.5
Values are expressed as mean ± SD (95% confidence interval). *Significant differences between both groups of patients with multiple sclerosis and controls (2-way ANCOVA test, P < 0.001).
r = 0.423; P = 0.05; nondominant: r = 0.338; P = 0.029), supraorbital (dominant: r = 0.362; P = 0.017; nondominant: r = 0.379; P = 0.020); infraorbital (dominant: r = 0.484; P = 0.001; nondominant: r = 0.428; P = 0.004); and mental (dominant r = 0.296; P = 0.049; nondominant: r = 0.328; P = 0.032) nerves, and over the second metacarpal (dominant: r = 0.373; P = 0.014; nondominant: r = 0.425; P = 0.004): the larger the area of perceived pain, the lower the widespread PPT. No significant correlation between the intensity of pain, disease (pain) duration, EDSS, or general fatigue with widespread pressure pain hyperalgesia was found in MS individuals with pain (all, Ps > 0.196).
DISCUSSION The current study identified the presence of widespread pressure hyperalgesia in patients with MS compared with pain-free controls, irrespective of the presence of pain. Patients with MS exhibited widespread pressure pain hyperalgesia. Our results suggest that MS can be associated with sensory hyperexcitability of the central nervous system or dysfunction in endogenous pain modulatory systems.
Widespread Pressure Pain Hyperalgesia in Patients With MS PPT was found to be significantly decreased bilaterally over nerve trunks in the trigeminal area and the upper extremity suggesting both trigeminal and extratrigeminal
sensitization of afferent inputs in MS possible as a sign of pain hyperexcitability.14 A significant widespread decrease in PPT over other points (C5-C6, second metacarpal, and tibialis anterior muscle) was also present suggesting the widespread manifestations of sensitization. The data supporting an excitability of the central nervous system in MS agree with previous studies showing thermal pain hyperalgesia in this population.8–13 The present study is the first one to report widespread pressure hypersensitivity in a MS both with and without pain compared with a control group. The presence of mechanical hyperalgesia in this condition is also supported by animal models mimicking MS with experimental autoimmune encephalomyelitis.33,34 A lower PPT was found in women compared with men as in agreement with a recent literature review.35 Lynch et al36 observed, in an animal pain model mimicking MS that female mice developed mechanical allodynia at a faster rate and displayed significantly more mechanical allodynia than male mice. As age-matched and sex-matched controls were included in our study, the observed differences in widespread pressure pain hyperalgesia cannot be explained by sex differences. The exact mechanisms underlying the widespread hyperalgesia in MS are not known. It has been hypothesized that lesions of the spinothalamocortical pathways could result in a disinhibition of pain pathways or an imbalance between nociceptive sensory inputs.37,38 Dysfunctional state of endogenous pain modulatory systems in MS has so far not been studied in detail. It has been found
TABLE 3. Differences in Pressure Pain Thresholds (kPa) Over the Median, Radial, and Ulnar Nerve Trunks Between Patients With Multiple Sclerosis With and Without Pain and Pain-free Controls
Median Nerve* Patients with multiple sclerosis with pain (n = 58) Dominant 254.1 ± 57.8 Nondominant 241.2 ± 52.3 Patients with multiple sclerosis without pain (n = 50) Dominant 264.9 ± 46.5 Nondominant 238.4 ± 50.3 Healthy controls (n = 108) Dominant 358.3 ± 52.3 Nondominant 356.8 ± 45.1
Radial Nerve*
Ulnar Nerve*
(240.1-268.0) (227.2-255.1)
262.0 ± 63.4 (246.7-277.3) 268.2 ± 62.8 (252.9-283.4)
349.7 ± 57.9 (335.1-364.3) 351.6 ± 62.2 (337.1-366.0)
(251.9-277.8) (225.4-251.3)
265.4 ± 47.6 (251.4-279.5) 265.8 ± 53.8 (251.8-279.8)
367.8 ± 52.5 (354.4-381.2) 364.2 ± 52.1 (350.8-377.6)
(348.8-367.7) (347.3-366.3)
380.8 ± 51.8 (370.5-391.1) 389.2 ± 51.2 (378.9-399.4)
441.7 ± 48.3 (431.8-451.5) 436.6 ± 47.2 (426.7-446.4)
Values are expressed as mean ± SD (95% confidence interval). *Significant differences between both groups of patients with multiple sclerosis and controls (2-way ANCOVA test, P < 0.001).
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TABLE 4. Differences in Pressure Pain Thresholds (kPa) Over the C5-C6 Joint, Second Metacarpal and Tibialis Anterior Muscle Between Patients With Multiple Sclerosis With and Without Pain and Pain-free Controls
C5-C6 Joint* Patients with multiple sclerosis with pain (n = 58) Dominant 199.4 ± 41.3 Nondominant 194.2 ± 40.6 Patients with multiple sclerosis without pain (n = 50) Dominant 201.8 ± 34.2 Nondominant 196.8 ± 36.2 Healthy controls (n = 108) Dominant 295.1 ± 43.4 Nondominant 292.5 ± 42.6
Second Metacarpal*
Tibialis Anterior*
(188.2-210.7) (183.0-205.5)
313.9 ± 64.4 (300.5-327.4) 317.1 ± 56.2 (303.6-330.4)
348.5 ± 60.7 (324.5-372.6) 360.6 ± 67.3 (336.6-384.7)
(191.3-212.4) (186.2-207.3)
332.1 ± 47.1 (319.6-344.5) 323.2 ± 49.4 (310.7-335.6)
374.4 ± 58.0 (352.0-396.7) 367.4 ± 59.1 (345.1-389.7)
(287.4-302.7) (284.9-300.2)
426.5 ± 41.3 (417.4-435.7) 427.7 ± 41.6 (418.6-436.9)
592.8 ± 68.6 (576.4-609.1) 592.0 ± 69.9 (575.6-608.4)
Values are expressed as mean ± SD (95% confidence interval). *Significant differences between both groups of patients with multiple sclerosis and controls (2-way ANCOVA test, P < 0.001).
that pathologically myelinated neurons exhibit increased excitability explaining sensory abnormalities observed in MS patients.39 Pain perceived by patients with MS has been suggested to be related to high-frequency bursts generated in demyelinated Ab-fibers.6 Whether these ectopic bursts in demyelinated Ab-fibers are sufficient to provoke pain per se or whether they do after elapsing transmission to neighboring nociceptive fibers or by involving wide dynamic range neurons remain unclear. Widespread hypersensitivity in MS could as such be a result of as well peripheral as central changes.
Differences Between MS Patients With and Without Pain Widespread pressure hypersensitivity was similar between patients with and without pain. This was an unexpected finding as ongoing pain is generally necessary for the development of central sensitization, and hence widespread hypersensitivity.7 In fact, previous studies investigating the presence of widespread pressure hypersensitivity as a manifestation of abnormal processing were conducted in populations with ongoing pain.15–19,21 All these studies support the theory that pain/nociception is a necessary prestep before central sensitization, and widespread hypersensitivity occur. The presence of pain was common (54%) in the current MS population, and the characteristics and location of the pain were similar to those previously reported in other studies.1–5 Our findings are similar to those previously observed by Grasso et al,10 however, contrary to those reported by Svendsen et al.12 Discrepancies between these studies can be related to the method of assessment and the body area where the pressure thresholds were assessed. We investigated the presence of widespread pressure hypersensitivity, whereas Svendsen et al12 assessed PPT over the site of pain. It is possible that pressure pain hyperalgesia is more pronounced in the site of ongoing pain. It is important to note, that patients with MS included in our nonpain group did not report previous episodes of pain, at least, in the previous 5 years before the study. This finding would support that the presence of widespread pressure hypersensitivity in patients with MS may be not related to the presence of pain which is highly unexpected. Vela et al20 observed generalized pressure pain hyperalgesia in individuals with Parkinson disease particularly within the OFF state. This study also reported no clear differences in generalized pressure pain hypersensitivity between r
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individuals with or without pain.20 Authors of this study determined that it is possible that in neurological conditions, such as Parkinson disease, the structural lesions accounting within the central nervous system cause a state of hyperexcitability without the presence of ongoing pain. This hypothesis would support the lack of differences in widespread pressure hypersensitivity observed between MS patients with and without pain. Finally, we also observed that MS patients with pain exhibited higher depression and fatigue levels than those without pain which agrees with previous studies11 and can affect the results.40 Further, although the presence of pressure hypersensitivity was not related to the presence of pain, it was higher in those patients with larger areas of pain. It is possible that a complex interaction exists among pain, self-rated general fatigue, depression, and sensory disturbances in individuals with MS.
Limitations First, the sample was composed of individuals with MS recruited from urban hospitals. Therefore, extrapolation of our results to more diverse populations should be conducted with caution. Second, we only assessed mechanical pain thresholds to determine sensory abnormalities. It would be of importance to perform a comprehensive sensory profiling of the MS patients utilizing a board spectrum of sensory tests combined with an assessment of descending modulation to investigate if different subpopulations exist.
CONCLUSIONS Widespread pressure pain hyperalgesia was identified in MS patients with and without pain as compared with Pain-free controls. No differences in pressure hyperalgesia existed between MS patients with pain and those without pain. Current results suggest that MS is associated with sensory hyperexcitability of the central nervous system and/ or dysfunction in endogenous pain modulatory systems. REFERENCES 1. Solaro C, Brichetto G, Amato MP, et al. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology. 2004;63:919–921. 2. Svendsen KB, Jensen TS, Overvad K, et al. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol. 2003;60:1089–1094.
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Widespread Pressure Pain Hypersensitivity in Patients With Multiple Sclerosis With and Without Pain as Sign of Central Sensitization Ce´sar Ferna´ndez-de-las-Pen˜as, PT, PhD, DMSc,*wz Ricardo Ortega-Santiago, PT, PhD,*w Rosa Ortı´z-Gutie´rrez, PT, PhD,y Ana B. Caminero, MD,8 Jaime Salom-Moreno, PT, PhD,*w and Lars Arendt-Nielsen, DMSc, PhDz
Objective: To determine the presence of widespread pressure hyperalgesia in multiple sclerosis (MS) patients with and without pain and its association with pain and fatigue. Methods: A total of 108 individuals with definite MS, 49 men and 59 women (mean age, 44 ± 8 y) and 108 age-matched and sexmatched pain-free controls (mean age, 44 ± 9 y) were included. Fifty patients (n = 58, 54%) reported pain and 50 (46%) did not. Pressure pain threshold (PPT) was bilaterally assessed over supraorbital, infraorbital, mental, median, radial and ulnar nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscle by an assessor blinded to the patient’s condition. The intensity of pain was assessed with a numerical pain rate scale (0 to 10), fatigue was determined with the Fatigue Impact Scale, and depression was evaluated with the Beck Depression Inventory. Results: The analyses of covariance revealed that PPT were significantly decreased bilaterally over the supraorbital, infraorbital, mental, median, ulnar and radial nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscles in patients with MS compared with pain-free controls (all, P < 0.001). No significant differences existed between MS patients with pain and those without pain (all P > 0.944). Patients with pain exhibited higher fatigue and depression than those patients without pain (P < 0.05). PPT was not associated with any clinical variable, that is, pain, depression, or fatigue. Conclusions: Our study found widespread pressure pain hyperalgesia in individuals with MS as compared with pain-free controls. No differences existed between MS patients with pain and those without pain in the presence of widespread pressure sensitivity. Current results suggest that MS is associated with sensory hyperexcitability of the central nervous system or dysfunction in endogenous pain modulatory systems. Key Words: multiple sclerosis, pressure pain threshold, sensitization, pain
(Clin J Pain 2015;31:66–72) Received for publication November 11, 2013; revised February 19, 2014; accepted January 28, 2014. From the *Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, Alcorco´n; yDepartment of Physical Therapy, Universidad Antonio de Nebrija; wLaboratory of Esthesiology, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorco´n, Madrid; 8Department of Neurology, Hospital Nuestra Sen˜ora de Sonsoles, Avila, Spain; and zDepartment of Health Science and Technology, Centre for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark. The authors declare no conflict of interest. Reprints: Ce´sar Ferna´ndez-de-las-Pen˜as, PT, PhD, DMSc, Laboratory of Esthesiology, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avenida de Atenas s/n, Alcorco´n 28922, Madrid, Spain (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins DOI: 10.1097/AJP.0000000000000084
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P
ain is a key symptom experienced by many individuals with multiple sclerosis (MS) and has started to receive increased attention in the recent years. Several patients with MS who experience pain describe it as one of the worst symptoms they had. The prevalence rate of pain in MS ranges from 29% to 82% depending on the country and the type of pain considered.1–4 A recent meta-analysis has pooled an overall pain prevalence of 63% (55% to 70%).5 As pain is associated to impaired quality of life and disability and represents an important therapeutic target in patients with MS, a better understanding of the mechanisms involved could contribute to the development of potential treatment strategies. Although the mechanisms underlying pain in MS have not yet been clarified, it has been linked to changes of the central pathways. Some theories explaining pain in MS suggest that injury of spinothalamic pathway results in a disinhibition of descending pain pathways or an imbalance between different inputs, and that structural lesions in the central nervous system cause a state of hyperexcitability (central sensitization) by increasing neuronal activity (spontaneous or evoked) at the site of injury and at remote sites.6 Central sensitization is usually assessed with quantitative sensory testing (eg, vibration, thermal, mechanical/ pressure, or electrical) being the assessment of pressure pain thresholds (PPTs) the most common way of assessing pain transmission, particularly in musculoskeletal chronic conditions.7 Some studies have investigated nociceptive processing in patients with MS and observed abnormalities in thermal pain thresholds.8–10 Leocani et al11 reported that patients with MS exhibited deficits in vibration thresholds as compared with healthy people and Svendsen et al12 showed that MS patients with pain exhibited lower PPTs and cold allodynia over the site of pain than patients without pain. A more recent study has confirmed that patients with MS and pain exhibit abnormal thermal detection thresholds.13 All these studies suggest the presence of abnormal nociceptive transmission in individuals with MS. However, these studies investigated quantitative sensory tests in one region and most of them investigated just thermal thresholds. To further confirm the presence of abnormal nociceptive transmission in MS, quantitative sensory tests should be investigated in several areas to investigate for widespread sensitization. It has been suggested that the presence of widespread pressure hyperalgesia over different tissues reflects a sign of abnormal pain processing.14 Several studies have observed the presence of widespread pressure pain hyperalgesia as a manifestation of abnormal nociceptive processing in musculoskeletal pain (eg, headache, fibromyalgia, Clin J Pain
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temporomandibular pain),15–18 neuropathic pain (eg, carpal tunnel syndrome),19 and neurological disorders (eg, Parkinson disease).20 The presence of widespread pressure pain hypersensitivity has been associated with poorer prognosis in individuals with chronic whiplash-associated disorders.21 There is no study investigating whether widespread pressure pain hypersensitivity over deep tissues is a feature of individuals with MS with pain and those without pain as manifestation of central sensitization process. The aim of our study was to investigate widespread pressure pain hyperalgesia in MS patients with and without pain and its association with clinical pain intensity and self-reported general fatigue.
METHODS Participants Consecutive individuals with definite MS according to the modified McDonald criteria and diagnosis by experienced neurologists were enrolled in the current study.22 Patients with MS with and without pain were included. Both neurogenic and non-neurogenic pain lasting for >3 months and of intensity >3 on a numerical pain rate scale (0 to 10) were considered. The exclusion criteria included other known neurological diseases, including herniated disk and other disorders of the spine, renal diseases, cancer, diabetes mellitus, severe psychiatric disease, and a Mini Mental State Examination score of 0.05). Differences in demographic and clinical variables among the groups were assessed with a 1-way analysis of variance (ANOVA). Demographic (age, sex, height, weight) and clinical variables (pain, fatigue) were entered as covariates in later analyses. Separated 3-way analyses of covariance (ANCOVA) were used to investigate the differences in PPT with point (C5-C6, second metacarpal, tibialis anterior, supraorbital, infraorbital, mental, median, and radial and ulnar nerves) and side (dominant, nondominant) as the within-subject factors and group (MS with pain, MS without pain, controls) as between-subjects factor. Post hoc comparisons were carried out with the Tukey test. The Pearson correlation test (r) was used to determine the association between PPTs and the clinical variables relating to pain symptoms and fatigue. The statistical analysis was conducted at a 95% confidence level and a P value 0.715). The post hoc analysis revealed that MS patients exhibited bilateral lower PPT than pain-free controls (all, P < 0.001), without differences between those with and without pain (all, P > 0.926) The inclusion of any
TABLE 1. Clinical and Demographic Characteristics of Patients With MS With and Without Pain and Healthy Controls
Demographic data Sex (M/F) Age (y) Height (cm) Weight (kg) Clinical data of patients with Disease duration (y) Disease course [n (%)] Relapsing remitting Secondary progressive Primary progressive EDDS (0-10) FIS (total score, 0-84) BDI-II (0-21)
MS With Pain (n = 58)
MS Without Pain (n = 50)
Pain-free Controls (n = 108)
P
29/29 44 ± 8 (41-46) 169.9 ± 9.6 (167.4-172.6) 72.2 ± 14.4 (67.7-76.6) MS 13.1 ± 8.4 (10.9-15.3)
20/30 45 ± 7 (43-47) 169.5 ± 9.1 (166.9-172.2) 70.3 ± 13.2 (66.5-74.2)
49/59 44 ± 8 (43-46) 168.7 ± 9.7 (166.8-170.6) 70.0 ± 13.1 (67.6-73.7)
w2 = 1.104; P = 0.576 F = 0.555; P = 0.575 F = 0.350; P = 0.705 F = 0.814; P = 0.444
12.4 ± 7.5 (10.3-14.6)
—
t = 0.477; P = 0.634
42 10 5 3.7 ± 1.8 43.6 ± 20.6 11.7 ± 6.9
38 9 3 3.4 ± 1.7 35.5 ± 18.8 9.3 ± 6.2
—
w2 = 3.008; P = 0.390
— — —
t = 0.937; P = 0.351 t = 2.130; P = 0.035 t = 2.005; P = 0.047
(73) (18) (9) (3.3-4.2) (37.7-49.5) (9.7-13.6)
(76) (18) (6) (2.9-3.9) (30.5-40.4) (7.7-11.0)
Data are expressed as means ± SD (95% confidence interval). BDI-I indicates Beck Depression Inventory; EDDS, Expanded Disability Status Scale; FIS, Fatigue Impact Scale; MS, multiple sclerosis.
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FIGURE 1. Areas of sensory pain symptoms in patients with multiple sclerosis.
clinical variable as covariate did not influence the results with exception of sex (all, P < 0.01): PPT were lower in female than in male in all the groups. Table 2 summarizes PPT assessed over the trigeminal nerve trunks and Table 3 shows PPT over upper extremity nerve trunks in both sides in the 3 groups.
Pressure Pain Sensitivity Over Non-Neural Tissues ANCOVA revealed significant differences between groups, but not between sides, for PPT over C5-C6 joint (group: F = 162.117; P < 0.001; side: F = 1.051; P = 0.306), second metacarpal (group: F = 129.028; P < 0.001; side: F = 0.099, P = 0.754), and tibialis anterior muscle (group: F = 187.806; P < 0.001; side: F = 0.027; P = r
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0.870). No significant side and group interaction was either found (all, P > 0.585). Post hoc analyses revealed that MS patients exhibited bilateral lower PPT than pain-free controls (all, P < 0.001), but without differences between those with and without pain (all, P > 0.944). The inclusion of any clinical variable as covariate did not influence the results, again with exception of sex (all, P < 0.01): PPTs were lower in female than in male in the 3 groups. Table 4 details PPT over C5-C6 zygapophyseal joints, second metacarpal, and tibialis anterior muscles in both the sides in all groups.
Clinical Features and Widespread Pressure Sensitivity in Patients With MS With Pain In MS patients with pain, the area of perceived pain was negatively associated with PPT over radial (dominant: www.clinicalpain.com |
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TABLE 2. Differences in Pressure Pain Thresholds (kPa) Over the Supraorbital, Infraorbital, and Mental Nerve Trunks Between Patients With Multiple Sclerosis With and Without Pain and Pain-free Controls
Supraorbital Nerve*
Infraorbital Nerve*
Mental Nerve*
183.5 ± 44.4 (172.1-194.9) 184.5 ± 50.2 (173.1-195.8)
197.8 ± 53.2 (185.4-210.2) 203.3 ± 51.1 (190.9-215.7)
(161.9-179.5) (156.6-175.1)
180.4 ± 43.2 (169.9-190.8) 186.9 ± 54.9 (176.3-197.4)
191.9 ± 48.9 (180.5-203.5) 195.1 ± 50.2 (183.5-206.6)
(263.4-276.3) (264.1-277.0)
286.1 ± 33.6 (278.4-293.9) 284.9 ± 29.4 (277.2-292.7)
296.0 ± 36.5 (287.6-304.5) 295.5 ± 38.4 (287.1-303.9)
Patients with multiple sclerosis with pain (n = 58) Dominant 175.5 ± 45.7 (166.0-184.9) Nondominant 174.1 ± 39.9 (164.5-183.6) Patients with multiple sclerosis without pain (n = 50) Dominant 170.7 ± 29.8 Nondominant 165.4 ± 28.6 Healthy controls (n = 108) Dominant 269.8 ± 31.3 Nondominant 270.6 ± 32.5
Values are expressed as mean ± SD (95% confidence interval). *Significant differences between both groups of patients with multiple sclerosis and controls (2-way ANCOVA test, P < 0.001).
r = 0.423; P = 0.05; nondominant: r = 0.338; P = 0.029), supraorbital (dominant: r = 0.362; P = 0.017; nondominant: r = 0.379; P = 0.020); infraorbital (dominant: r = 0.484; P = 0.001; nondominant: r = 0.428; P = 0.004); and mental (dominant r = 0.296; P = 0.049; nondominant: r = 0.328; P = 0.032) nerves, and over the second metacarpal (dominant: r = 0.373; P = 0.014; nondominant: r = 0.425; P = 0.004): the larger the area of perceived pain, the lower the widespread PPT. No significant correlation between the intensity of pain, disease (pain) duration, EDSS, or general fatigue with widespread pressure pain hyperalgesia was found in MS individuals with pain (all, Ps > 0.196).
DISCUSSION The current study identified the presence of widespread pressure hyperalgesia in patients with MS compared with pain-free controls, irrespective of the presence of pain. Patients with MS exhibited widespread pressure pain hyperalgesia. Our results suggest that MS can be associated with sensory hyperexcitability of the central nervous system or dysfunction in endogenous pain modulatory systems.
Widespread Pressure Pain Hyperalgesia in Patients With MS PPT was found to be significantly decreased bilaterally over nerve trunks in the trigeminal area and the upper extremity suggesting both trigeminal and extratrigeminal
sensitization of afferent inputs in MS possible as a sign of pain hyperexcitability.14 A significant widespread decrease in PPT over other points (C5-C6, second metacarpal, and tibialis anterior muscle) was also present suggesting the widespread manifestations of sensitization. The data supporting an excitability of the central nervous system in MS agree with previous studies showing thermal pain hyperalgesia in this population.8–13 The present study is the first one to report widespread pressure hypersensitivity in a MS both with and without pain compared with a control group. The presence of mechanical hyperalgesia in this condition is also supported by animal models mimicking MS with experimental autoimmune encephalomyelitis.33,34 A lower PPT was found in women compared with men as in agreement with a recent literature review.35 Lynch et al36 observed, in an animal pain model mimicking MS that female mice developed mechanical allodynia at a faster rate and displayed significantly more mechanical allodynia than male mice. As age-matched and sex-matched controls were included in our study, the observed differences in widespread pressure pain hyperalgesia cannot be explained by sex differences. The exact mechanisms underlying the widespread hyperalgesia in MS are not known. It has been hypothesized that lesions of the spinothalamocortical pathways could result in a disinhibition of pain pathways or an imbalance between nociceptive sensory inputs.37,38 Dysfunctional state of endogenous pain modulatory systems in MS has so far not been studied in detail. It has been found
TABLE 3. Differences in Pressure Pain Thresholds (kPa) Over the Median, Radial, and Ulnar Nerve Trunks Between Patients With Multiple Sclerosis With and Without Pain and Pain-free Controls
Median Nerve* Patients with multiple sclerosis with pain (n = 58) Dominant 254.1 ± 57.8 Nondominant 241.2 ± 52.3 Patients with multiple sclerosis without pain (n = 50) Dominant 264.9 ± 46.5 Nondominant 238.4 ± 50.3 Healthy controls (n = 108) Dominant 358.3 ± 52.3 Nondominant 356.8 ± 45.1
Radial Nerve*
Ulnar Nerve*
(240.1-268.0) (227.2-255.1)
262.0 ± 63.4 (246.7-277.3) 268.2 ± 62.8 (252.9-283.4)
349.7 ± 57.9 (335.1-364.3) 351.6 ± 62.2 (337.1-366.0)
(251.9-277.8) (225.4-251.3)
265.4 ± 47.6 (251.4-279.5) 265.8 ± 53.8 (251.8-279.8)
367.8 ± 52.5 (354.4-381.2) 364.2 ± 52.1 (350.8-377.6)
(348.8-367.7) (347.3-366.3)
380.8 ± 51.8 (370.5-391.1) 389.2 ± 51.2 (378.9-399.4)
441.7 ± 48.3 (431.8-451.5) 436.6 ± 47.2 (426.7-446.4)
Values are expressed as mean ± SD (95% confidence interval). *Significant differences between both groups of patients with multiple sclerosis and controls (2-way ANCOVA test, P < 0.001).
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TABLE 4. Differences in Pressure Pain Thresholds (kPa) Over the C5-C6 Joint, Second Metacarpal and Tibialis Anterior Muscle Between Patients With Multiple Sclerosis With and Without Pain and Pain-free Controls
C5-C6 Joint* Patients with multiple sclerosis with pain (n = 58) Dominant 199.4 ± 41.3 Nondominant 194.2 ± 40.6 Patients with multiple sclerosis without pain (n = 50) Dominant 201.8 ± 34.2 Nondominant 196.8 ± 36.2 Healthy controls (n = 108) Dominant 295.1 ± 43.4 Nondominant 292.5 ± 42.6
Second Metacarpal*
Tibialis Anterior*
(188.2-210.7) (183.0-205.5)
313.9 ± 64.4 (300.5-327.4) 317.1 ± 56.2 (303.6-330.4)
348.5 ± 60.7 (324.5-372.6) 360.6 ± 67.3 (336.6-384.7)
(191.3-212.4) (186.2-207.3)
332.1 ± 47.1 (319.6-344.5) 323.2 ± 49.4 (310.7-335.6)
374.4 ± 58.0 (352.0-396.7) 367.4 ± 59.1 (345.1-389.7)
(287.4-302.7) (284.9-300.2)
426.5 ± 41.3 (417.4-435.7) 427.7 ± 41.6 (418.6-436.9)
592.8 ± 68.6 (576.4-609.1) 592.0 ± 69.9 (575.6-608.4)
Values are expressed as mean ± SD (95% confidence interval). *Significant differences between both groups of patients with multiple sclerosis and controls (2-way ANCOVA test, P < 0.001).
that pathologically myelinated neurons exhibit increased excitability explaining sensory abnormalities observed in MS patients.39 Pain perceived by patients with MS has been suggested to be related to high-frequency bursts generated in demyelinated Ab-fibers.6 Whether these ectopic bursts in demyelinated Ab-fibers are sufficient to provoke pain per se or whether they do after elapsing transmission to neighboring nociceptive fibers or by involving wide dynamic range neurons remain unclear. Widespread hypersensitivity in MS could as such be a result of as well peripheral as central changes.
Differences Between MS Patients With and Without Pain Widespread pressure hypersensitivity was similar between patients with and without pain. This was an unexpected finding as ongoing pain is generally necessary for the development of central sensitization, and hence widespread hypersensitivity.7 In fact, previous studies investigating the presence of widespread pressure hypersensitivity as a manifestation of abnormal processing were conducted in populations with ongoing pain.15–19,21 All these studies support the theory that pain/nociception is a necessary prestep before central sensitization, and widespread hypersensitivity occur. The presence of pain was common (54%) in the current MS population, and the characteristics and location of the pain were similar to those previously reported in other studies.1–5 Our findings are similar to those previously observed by Grasso et al,10 however, contrary to those reported by Svendsen et al.12 Discrepancies between these studies can be related to the method of assessment and the body area where the pressure thresholds were assessed. We investigated the presence of widespread pressure hypersensitivity, whereas Svendsen et al12 assessed PPT over the site of pain. It is possible that pressure pain hyperalgesia is more pronounced in the site of ongoing pain. It is important to note, that patients with MS included in our nonpain group did not report previous episodes of pain, at least, in the previous 5 years before the study. This finding would support that the presence of widespread pressure hypersensitivity in patients with MS may be not related to the presence of pain which is highly unexpected. Vela et al20 observed generalized pressure pain hyperalgesia in individuals with Parkinson disease particularly within the OFF state. This study also reported no clear differences in generalized pressure pain hypersensitivity between r
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individuals with or without pain.20 Authors of this study determined that it is possible that in neurological conditions, such as Parkinson disease, the structural lesions accounting within the central nervous system cause a state of hyperexcitability without the presence of ongoing pain. This hypothesis would support the lack of differences in widespread pressure hypersensitivity observed between MS patients with and without pain. Finally, we also observed that MS patients with pain exhibited higher depression and fatigue levels than those without pain which agrees with previous studies11 and can affect the results.40 Further, although the presence of pressure hypersensitivity was not related to the presence of pain, it was higher in those patients with larger areas of pain. It is possible that a complex interaction exists among pain, self-rated general fatigue, depression, and sensory disturbances in individuals with MS.
Limitations First, the sample was composed of individuals with MS recruited from urban hospitals. Therefore, extrapolation of our results to more diverse populations should be conducted with caution. Second, we only assessed mechanical pain thresholds to determine sensory abnormalities. It would be of importance to perform a comprehensive sensory profiling of the MS patients utilizing a board spectrum of sensory tests combined with an assessment of descending modulation to investigate if different subpopulations exist.
CONCLUSIONS Widespread pressure pain hyperalgesia was identified in MS patients with and without pain as compared with Pain-free controls. No differences in pressure hyperalgesia existed between MS patients with pain and those without pain. Current results suggest that MS is associated with sensory hyperexcitability of the central nervous system and/ or dysfunction in endogenous pain modulatory systems. REFERENCES 1. Solaro C, Brichetto G, Amato MP, et al. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology. 2004;63:919–921. 2. Svendsen KB, Jensen TS, Overvad K, et al. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol. 2003;60:1089–1094.
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3. Grau-Lo´pez L, Sierra S, Martı´ nez-Ca´ceres E, et al. Analysis of the pain in multiple sclerosis patients. Neurologia. 2011;26: 208–213. 4. O’Connor AB, Schwid SR, Herrmann DN, et al. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain. 2008;137:96–111. 5. Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154:632–642. 6. Truini A, Galeotti F, La Cesa S, et al. Mechanisms of pain in multiple sclerosis: a combined clinical and neurophysiological study. Pain. 2012;153:2048–2054. 7. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain. 2011;152:S2–S15. 8. Merchut MP, Gruener G. Quantitative sensory threshold testing in patients with multiple sclerosis. Electromyogr Clin Neurophysiol. 1993;33:119–124. 9. Osterberg A, Boivie J, Holmgren H, et al. The clinical characteristics and sensory abnormalities in patients with central pain caused by multiple sclerosis. In: Gebhart GF, Hammond DL, Jensen TS, eds. Proceedings of the Seventh World Congress on Pain. Seattle, WA: IASP Press; 1994: 789–796. 10. Grasso MG, Clemenzi A, Tonini A, et al. Pain in multiple sclerosis: a clinical and instrumental approach. Mult Scler. 2008;14:506–513. 11. Leocani L, Martinelli V, Natali-Sora MG, et al. Somatosensory evoked potentials and sensory involvement in multiple sclerosis: comparison with clinical findings and quantitative sensory tests. Mult Scler. 2003;9:275–279. 12. Svendsen KB, Jensen TS, Hansen HJ, et al. Sensory function and quality of life in patients with multiple sclerosis and pain. Pain. 2005;114:473–481. 13. Osterberg A, Boivie J. Central pain in multiple sclerosis: sensory abnormalities. Eur J Pain. 2010;14:104–110. 14. Zusman M. Central nervous system contribution to mechanically produced motor and sensory responses. Aus J Physiother. 1992;38:195–20. 15. Montoya P, Pauli P, Batra A, et al. Altered processing of painrelated information in patients with fibromyalgia. Eur J Pain. 2005;9:293–303. 16. Ferna´ndez-Carnero J, Ferna´ndez-de-las-Pen˜as C, De-LaLlave-Rinco´n AI, et al. Widespread mechanical pain hypersensitivity as sign of central sensitization in unilateral lateral epicondylalgia: a blinded, controlled study. Clin J Pain. 2009;25:555–561. 17. Ferna´ndez-de-las-Pen˜as C, Arendt-Nielsen L, Cuadrado ML, et al. Generalized mechanical pain sensitivity over nerve tissues in patients with strictly unilateral migraine. Clin J Pain. 2009;25:401–406. 18. Ferna´ndez-de-las-Pen˜as C, Gala´n-del-Rı´ o F, Ferna´ndez-Carnero J, et al. Bilateral widespread mechanical pain sensitivity in myofascial temporomandibular disorder: evidence of impairment in central nociceptive processing. J Pain. 2009;10: 1170–1178. 19. Ferna´ndez-de-las-Penas C, de la Llave-Rincon AI, FernandezCarnero J, et al. Bilateral widespread mechanical pain sensitivity in carpal tunnel syndrome: evidence of central processing in unilateral neuropathy. Brain. 2009;132: 1472–1479. 20. Vela L, Cano-de-la-Cuerda R, Fil A, et al. Thermal and mechanical pain thresholds in patients with fluctuating
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