Transcranial Direct Current Stimulation Potentiates the effects of Electrical
Intramuscular Stimulation at Relieving Pain and Improving the Descending Pain
Modulatory System in Patients with Knee Osteoarthritis: A Randomized,
Double-Blinded, Factorial Design and Sham-Controlled Study
Aluna: Maria da Graça Lopes Tarragó
Orientador: Prof. Dr. Wolnei Caumo
Parcial da Tese de Doutorado
2017
Universidade Federal do Rio Grande do Sul
Programa de Pós-Graduação em Medicina: Ciências Médicas
Faculdade de Medicina
ESTUDO 3
ARTIGO SUBMETIDO
FATOR DE IMPACTO: 6.078
Transcranial Direct Current Stimulation Potentiates the effects of
Electrical Intramuscular Stimulation at Relieving Pain and Improving
the Descending Pain Modulatory System in Patients with Knee
Osteoarthritis: A Randomized, Double-Blinded, Factorial Design and
Sham-Controlled Study
Maria da Graca-Tarragó, Mateus Lech, Letícia Dal Moro Angoleri, Daniela
Silva Santos, Alícia Deitos, Aline Patrícia Brietzke, Iraci L. S. Torres, Felipe
INTRODUÇÃO
EPIDEMIOLOGIA
OSTEOARTRITE (OA)
Imamura M 2015, Mascarin NC 2012,Chang WJ 2015, Emrani PS 2008, Reinhold T 2008.
Evidência radiológica de OA
85% da população 65 anos
⬇︎Qualidade de vida
⬆︎Risco incapacidade em idosos
Impacto nas atividades diárias
Principal causa de morbidade
APRESENTAÇÃO CLÍNICA
OSTEOARTRITE
Locais mais acometidos:
Joelhos, mãos, pés
Coluna vertebral, quadris
A OA de joelho é a principal causa de incapacidade e dor em
pacientes idosos
Tratamento atual apresenta eficácia limitada
FISIOPATOLOGIA: PROCESSAMENTO DA DOR NA OSTEOARTRITE
Neuroplasticidade
mal-adaptativa
Facilitação
Inibição
FISIOPATALOGIA: FENÔMENO DE SENSIBILIZAÇÃO CENTRAL
Woolf CJ et al. Neuronal plasticity: increasing the gain in pain. Science, 2000
DOR
•
Principal marcador do processo de plasticidade neuronal
•
Neurogênese, anti-inflamatório, reduz apoptose celular
•
BDNF favorece a long term potentiation (LTP)
BDNF: FATOR NEUROTRÓFICO DERIVADO DO CÉREBRO
Imamura M 2015, Mascarin NC 2012,Chang WJ 2015, Emrani PS 2008, Reinhold T 2008.
OBJETIVO
ESTUDO 3
1.
Avaliar o efeito sinérgico da ETCC e da EIMS sob os
níveis de dor e capacidade funcional de pacientes
com OA.
metodologia
•
Dor diária (0 - 10)
ESCALA NUM
ÉRICA
DE DOR – NPS
•
Doses semanais consumidas nos
últimos 3 meses
ANALG
ÉSICOS
•
Dor, rigidez e capacidade funcional
WOMAC
METODOLOGIA
METODOLOGIA
Resolução 466/2012 CNS
AVALIAÇÃO DA POTÊNCIA DO SISTEMA MODULATÓRIO DESCENDENTE DA DOR
Imamura 2012, Moont 2011, Edwards 2003
TESTE DE DOR CONDICIONADA (CPM – TASK)
INTERVENÇÃO
ESTIMULAÇÃO ELÉTRICA INTRAMUSCULAR (EIMS)
ESTMULAÇÃO ATIVA
•
Agulhas de acupuntura
•
Inserção profunda
•
2Hz
•
30min
ESTMULAÇÃO SIMULADA
•
Eletrodos de borracha com gel condutor
•
Mesmo eletro estimulador
•
SEM passagem de corrente
INTERVENÇÃO
ESTIMULAÇÃO TRANSCRANIANA DE CORRENTE CONTÍNUA (ETCC)
ESTMULAÇÃO ATIVA
•
Ânodo: M1contralateral
•
Cátodo: SO
•
2 mA
•
30 min
ESTMULAÇÃO SIMULADA
•
30 seg estimulação
•
Mesmo aparelho
•
SEM passagem de
corrente
•
30 min
Transcranial Direct Current Stimulation (tDCS)
•
Non-invasive, portable, well-tolerated
neuromodulation.
•
Low-intensity (mA) current passed
between scalp electrodes.
•
Tested for cognitive neuroscience and
neuropsychiatric treatment.
tDCS Publications
+
U%
How do we optimize tDCS for a specific indication and individual
tDCS electrode position on the head
determines which regions are stimulated
!
Current flows from one electrode to the other
Tr uong et al. Clinician accessible tools for GUI computational
models
. “BONSAI ” and “SPH ERES”. Brain Stimulation 2014
Zero Max
Extra-cephalic electrode won’t solve
the issue of diffuse bi-directional flow
!
tDCS is deep
Datta et al. Electrode montage for tDCS: Role of retur n electrode.
Clinical N europhysiology 2010
Datta et al. Electrode montage for tDCS: Role of retur n electrode.
Clinical N europhysiology 2010
Extra-cephalic electrode won’t solve
the issue of diffuse bi-directional flow
!
tDCS is deep
Bikson, 2015
Peletier, SJ. Et al.,2015. International Journal of Neuropsychopharmacology, 1–13
ESTUDO 3
TABELA 1. CARACTERÍSTICAS DEMOGRÁFICAS DA AMOSTRA (N=60)
RESULTADOS
Variable a-EI M S/atDCS (n=15) a-tDCS/sI M S (n=15) s-tDCS/aI M S (n(=15) s-tDCS/s-I M S (n=15) P Age (years) 66.00 (9.08) 64.14 (9.82) 64.40 (6.02) 63.87 (7.07) 0.88
Body Mass Index (kg/m2) 29.27(4.15) 29.47(3.69) 30.85(4.82) 28.83(3.85) 0.58
Employed (yes/no) (%) 2/14 (27.1%) 3/10 (22.0%) 1/14 (25.4%) 3/12(25.4%) 0.60
School years 7.75 (4.19) 8.32 (4.15) 9.13 (4.63) 6.20 (3.84) 0.28
Pain during the most part of days (VAS)
6.31 (1.14) 6.57 (0.51) 6.07 (1.39) 6.73 (0.46) 0.26
Psychiatric disease diagnosis (yes/no) 6/10(26.7) 6/8(23.3) 3/12(25.0) 5/10(25.0) 0.59 Psychotropic medication Yes/No (%)‡ 8(53.3) 8(53.3) 3(20) 7 (46.7) 0.41 Smoking (yes/no) (%) 2/14(26.7) 0/14(23.3) 0/15(25.0) 1/14(25.0) 0.32 Alcohol (yes/no) 4/12(27.1) 2/12(23.7) 2/13(25.4) 1/13(23.7) 0.58
Number of chronic disease 1(0.89) 1.5 (1.5) 1.8 (1.74) 1.4(0.83) 0.39
Type of chronic disease
Diabetic (yes/no) 2 (13.3) 2 (13.3) 3 (20) 4 (26.7)
Hypothyroidism (yes/no) 2 (13.3) 3 (20) 1(6.7) 1 (6.7)
Hypertension (yes/no) 8 (53.3) 7 (46.7) 10 (66.7) 13 (86.7)
Other (yes/no) 1(6.7) 0 2(13.3) 1(6.7)
WOMAC (total score) ¥ 54.75(19.80) 52.36(20.35) 54.13(18.56) 50.47(13.75) 0.95
W- stifness 4.93 (2.91) 4.50 (2.50) 4.93 (2.74) 4.33 (1.76) 0.88
W- daily activities 25.60 (10.87) 24.07 (10.55) 23.53 (10.68) 22.33 (9.72) 0.86
W- pain 10.93 (4.43) 10.64 (5.11) 11.80 (3.36) 10.87 (3.56) 0.88
Pain score in the VAS in the last 24 hours
5.59 (2.63) 6.07 (2.42) 5.27(1.91) 5.50 (2.77) 0.84
Beck Depression Inventory 14.75 (11.22) 12.64 (9.47) 11.07 (12.07) 8.53 (4.70) 0.36
Brazilian Portuguese Pain Catastrophizing
29.37(10.51) 28.86 (9.80) 22.27(13.22) 26.73(11.36) 0.30
Pittsburgh Sleep Quality Index Score
18.94 (13.73) 23.71 (14.08) 22.73 (12.25) 16.80 (12.72) 0.45
PPT in (kg/cm2/second) 2.81(1.41) 3.56(2.54) 3.71(2.81) 3.41(1.85) 0.72
TABELA 1. CARACTERÍSTICAS CLÍNICAS DA AMOSTRA (N=60)
RESULTADOS
Variable a-EI M S/atDCS (n=15) a-tDCS/sI M S (n=15) s-tDCS/aI M S (n(=15) s-tDCS/s-I M S (n=15) P Age (years) 66.00 (9.08) 64.14 (9.82) 64.40 (6.02) 63.87 (7.07) 0.88
Body Mass Index (kg/m2) 29.27(4.15) 29.47(3.69) 30.85(4.82) 28.83(3.85) 0.58
Employed (yes/no) (%) 2/14 (27.1%) 3/10 (22.0%) 1/14 (25.4%) 3/12(25.4%) 0.60
School years 7.75 (4.19) 8.32 (4.15) 9.13 (4.63) 6.20 (3.84) 0.28
Pain during the most part of days (VAS)
6.31 (1.14) 6.57 (0.51) 6.07 (1.39) 6.73 (0.46) 0.26
Psychiatric disease diagnosis (yes/no) 6/10(26.7) 6/8(23.3) 3/12(25.0) 5/10(25.0) 0.59 Psychotropic medication Yes/No (%)‡ 8(53.3) 8(53.3) 3(20) 7 (46.7) 0.41 Smoking (yes/no) (%) 2/14(26.7) 0/14(23.3) 0/15(25.0) 1/14(25.0) 0.32 Alcohol (yes/no) 4/12(27.1) 2/12(23.7) 2/13(25.4) 1/13(23.7) 0.58
Number of chronic disease 1(0.89) 1.5 (1.5) 1.8 (1.74) 1.4(0.83) 0.39
Type of chronic disease
Diabetic (yes/no) 2 (13.3) 2 (13.3) 3 (20) 4 (26.7)
Hypothyroidism (yes/no) 2 (13.3) 3 (20) 1(6.7) 1 (6.7)
Hypertension (yes/no) 8 (53.3) 7 (46.7) 10 (66.7) 13 (86.7)
Other (yes/no) 1(6.7) 0 2(13.3) 1(6.7)
WOMAC (total score) ¥ 54.75(19.80) 52.36(20.35) 54.13(18.56) 50.47(13.75) 0.95
W- stifness 4.93 (2.91) 4.50 (2.50) 4.93 (2.74) 4.33 (1.76) 0.88
W- daily activities 25.60 (10.87) 24.07 (10.55) 23.53 (10.68) 22.33 (9.72) 0.86
W- pain 10.93 (4.43) 10.64 (5.11) 11.80 (3.36) 10.87 (3.56) 0.88
Pain score in the VAS in the last 24 hours
5.59 (2.63) 6.07 (2.42) 5.27(1.91) 5.50 (2.77) 0.84
Beck Depression Inventory 14.75 (11.22) 12.64 (9.47) 11.07 (12.07) 8.53 (4.70) 0.36
Brazilian Portuguese Pain Catastrophizing
29.37(10.51) 28.86 (9.80) 22.27(13.22) 26.73(11.36) 0.30
Pittsburgh Sleep Quality Index Score
18.94 (13.73) 23.71 (14.08) 22.73 (12.25) 16.80 (12.72) 0.45
PPT in (kg/cm2/second) 2.81(1.41) 3.56(2.54) 3.71(2.81) 3.41(1.85) 0.72
Variable a-EI M S/atDCS (n=15) a-tDCS/sI M S (n=15) s-tDCS/aI M S (n(=15) s-tDCS/s-I M S (n=15) P Age (years) 66.00 (9.08) 64.14 (9.82) 64.40 (6.02) 63.87 (7.07) 0.88
Body Mass Index (kg/m2) 29.27(4.15) 29.47(3.69) 30.85(4.82) 28.83(3.85) 0.58
Employed (yes/no) (%) 2/14 (27.1%) 3/10 (22.0%) 1/14 (25.4%) 3/12(25.4%) 0.60
School years 7.75 (4.19) 8.32 (4.15) 9.13 (4.63) 6.20 (3.84) 0.28
Pain during the most part of days (VAS)
6.31 (1.14) 6.57 (0.51) 6.07 (1.39) 6.73 (0.46) 0.26
Psychiatric disease diagnosis (yes/no) 6/10(26.7) 6/8(23.3) 3/12(25.0) 5/10(25.0) 0.59 Psychotropic medication Yes/No (%)‡ 8(53.3) 8(53.3) 3(20) 7 (46.7) 0.41 Smoking (yes/no) (%) 2/14(26.7) 0/14(23.3) 0/15(25.0) 1/14(25.0) 0.32 Alcohol (yes/no) 4/12(27.1) 2/12(23.7) 2/13(25.4) 1/13(23.7) 0.58
Number of chronic disease 1(0.89) 1.5 (1.5) 1.8 (1.74) 1.4(0.83) 0.39
Type of chronic disease
Diabetic (yes/no) 2 (13.3) 2 (13.3) 3 (20) 4 (26.7)
Hypothyroidism (yes/no) 2 (13.3) 3 (20) 1(6.7) 1 (6.7)
Hypertension (yes/no) 8 (53.3) 7 (46.7) 10 (66.7) 13 (86.7)
Other (yes/no) 1(6.7) 0 2(13.3) 1(6.7)
WOMAC (total score) ¥ 54.75(19.80) 52.36(20.35) 54.13(18.56) 50.47(13.75) 0.95
W- stifness 4.93 (2.91) 4.50 (2.50) 4.93 (2.74) 4.33 (1.76) 0.88
W- daily activities 25.60 (10.87) 24.07 (10.55) 23.53 (10.68) 22.33 (9.72) 0.86
W- pain 10.93 (4.43) 10.64 (5.11) 11.80 (3.36) 10.87 (3.56) 0.88
Pain score in the VAS in the last 24 hours
5.59 (2.63) 6.07 (2.42) 5.27(1.91) 5.50 (2.77) 0.84
Beck Depression Inventory 14.75 (11.22) 12.64 (9.47) 11.07 (12.07) 8.53 (4.70) 0.36
Brazilian Portuguese Pain Catastrophizing
29.37(10.51) 28.86 (9.80) 22.27(13.22) 26.73(11.36) 0.30
Pittsburgh Sleep Quality Index Score
18.94 (13.73) 23.71 (14.08) 22.73 (12.25) 16.80 (12.72) 0.45
PPT in (kg/cm2/second) 2.81(1.41) 3.56(2.54) 3.71(2.81) 3.41(1.85) 0.72
FIGURA 2. COMPARAÇOES ENTRE GRUPOS PRÉ E PÓS TRATAMENTOS (N=60)
RESULTADOS
TABELA 2. MEDIDAS DE DOR E SISTEMA MODULATÓRIO DESCENDENTE DA DOR
(N=60)
RESULTADOS: DESFECHOS PRIMÁRIOS
M ean (SD) After intervention Before intervention CI 95% Wald χ2 Df Effect size P
Primary outcomes: The cumulative pain scores on VAS (0 -10cm) after intervention throughout the treatment (1) a-tDCS/a-IMS a (n= 15) 0.46 (0.04) 2,3,4 vs. 6.32 (1.97) -5.42 (-8.24 to -4.36) 8.69 3 0.57 0.03 (2) a-tDCS/ s-IMS b (n= 15) 1.79 (2.53) 1,4 vs. 6.52 (2.63) -4.73 (-7.65 to -3.11) (3) s-tDCS/a-IMS c (n= 15) 1.81 (2.98) 1,4 vs. 6.75 (2.62) -4.6 (-7.84 to -2.38) (4) s-tDCS/s-IMS d (n= 15) 2.98 (1.17) 1,2,3 vs. 7.17 (2.47) -4.19 (-8.10 to -2.93) Secondary outcomes:
b. Pressure pain threshold (PPT) in (kg/cm2/second)
(1) a-tDCS/a-IMS a (n= 15) 6.00 (1.76) vs . 3.24 (1.40) 2.96 (0.94 to 4.54) a 8.99 3 0.60 0.02 (2) a-tDCS/ s-IMS b (n= 15) 6.53 (3.27) vs . 3.86 (2.53) 2.67 (0.92 to 4.63) a (3) s-tDCS/a-IMS c (n= 15) 6.43 (3.38) vs . 3.76 (2.80) 2.67 (0.28 to 5.82) a (4) s-tDCS/s-IMS d (n= 15) 4.73 (1.37) vs . 2.95 (1.38) 1.78 (0.55 to 3.02) b WOM AC score (1) a-tDCS/a-IMS a (n= 15) 27.31 (23.19) vs . 54.75 (19.80) -27.44 (-38.41 to -16.46)a,b 8.48 3 0.56 0.03
(2) a-tDCS/ s-IMS b (n= 15) 32.50 (21.61) vs . 52.36 (20.35) -19.14 (-28.28 to -10.00)a
(3) s-tDCS/a-IMS c (n= 15) 22.13 (13.22) vs . 54.13 (18.56) -30.00 (-39.29 to -20.70)a,b
(4) s-tDCS/s-IMS d (n= 15) 46.60 (16.42) vs. 50.47 (13.74) -5.20 (-15.03 to 4.63)
TABELA 2. MEDIDAS DE DOR E CAPACIDADE FUNCIONAL (N=60)
RESULTADOS: DESFECHOS SECUNDÁRIOS
Data present as mean (SD).
M ean (SD) After intervention Before intervention CI 95% Wald χ2 Df Effect size P
Primary outcomes: The cumulative pain scores on VAS (0 -10cm) after intervention throughout the treatment (1) a-tDCS/a-IMS a (n= 15) 0.46 (0.04) 2,3,4 vs. 6.32 (1.97) -5.42 (-8.24 to -4.36) 8.69 3 0.57 0.03 (2) a-tDCS/ s-IMS b (n= 15) 1.79 (2.53) 1,4 vs. 6.52 (2.63) -4.73 (-7.65 to -3.11) (3) s-tDCS/a-IMS c (n= 15) 1.81 (2.98) 1,4 vs. 6.75 (2.62) -4.6 (-7.84 to -2.38) (4) s-tDCS/s-IMS d (n= 15) 2.98 (1.17) 1,2,3 vs. 7.17 (2.47) -4.19 (-8.10 to -2.93) Secondary outcomes:
b. Pressure pain threshold (PPT) in (kg/cm2/second)
(1) a-tDCS/a-IMS a (n= 15) 6.00 (1.76) vs . 3.24 (1.40) 2.96 (0.94 to 4.54) a 8.99 3 0.60 0.02 (2) a-tDCS/ s-IMS b (n= 15) 6.53 (3.27) vs . 3.86 (2.53) 2.67 (0.92 to 4.63) a (3) s-tDCS/a-IMS c (n= 15) 6.43 (3.38) vs . 3.76 (2.80) 2.67 (0.28 to 5.82) a (4) s-tDCS/s-IMS d (n= 15) 4.73 (1.37) vs . 2.95 (1.38) 1.78 (0.55 to 3.02) b WOM AC score (1) a-tDCS/a-IMS a (n= 15) 27.31 (23.19) vs . 54.75 (19.80) -27.44 (-38.41 to -16.46)a,b 8.48 3 0.56 0.03
(2) a-tDCS/ s-IMS b (n= 15) 32.50 (21.61) vs . 52.36 (20.35) -19.14 (-28.28 to -10.00)a
(3) s-tDCS/a-IMS c (n= 15) 22.13 (13.22) vs . 54.13 (18.56) -30.00 (-39.29 to -20.70)a,b (4) s-tDCS/s-IMS d (n= 15) 46.60 (16.42) vs. 50.47 (13.74) -5.20 (-15.03 to 4.63) M ean (SD) After intervention Before intervention CI 95% Wald χ2 Df Effect size P
Primary outcomes: The cumulative pain scores on VAS (0 -10cm) after intervention throughout the treatment (1) a-tDCS/a-IMS a (n= 15) 0.46 (0.04) 2,3,4 vs. 6.32 (1.97) -5.42 (-8.24 to -4.36) 8.69 3 0.57 0.03 (2) a-tDCS/ s-IMS b (n= 15) 1.79 (2.53) 1,4 vs. 6.52 (2.63) -4.73 (-7.65 to -3.11) (3) s-tDCS/a-IMS c (n= 15) 1.81 (2.98) 1,4 vs. 6.75 (2.62) -4.6 (-7.84 to -2.38) (4) s-tDCS/s-IMS d (n= 15) 2.98 (1.17) 1,2,3 vs. 7.17 (2.47) -4.19 (-8.10 to -2.93) Secondary outcomes:
b. Pressure pain threshold (PPT) in (kg/cm2/second)
(1) a-tDCS/a-IMS a (n= 15) 6.00 (1.76) vs . 3.24 (1.40) 2.96 (0.94 t o 4.54) a 8.99 3 0.60 0.02 (2) a-tDCS/ s-IMS b (n= 15) 6.53 (3.27) vs . 3.86 (2.53) 2.67 (0.92 t o 4.63) a (3) s-tDCS/a-IMS c (n= 15) 6.43 (3.38) vs . 3.76 (2.80) 2.67 (0.28 t o 5.82) a (4) s-tDCS/s-IMS d (n= 15) 4.73 (1.37) vs . 2.95 (1.38) 1.78 (0.55 to 3.02) b WOM AC score (1) a-tDCS/a-IMS a (n= 15) 27.31 (23.19) vs . 54.75 (19.80) -27.44 (-38.41 to -16.46)a,b 8.48 3 0.56 0.03
(2) a-tDCS/ s-IMS b (n= 15) 32.50 (21.61) vs . 52.36 (20.35) -19.14 (-28.28 to -10.00)a
(3) s-tDCS/a-IMS c (n= 15) 22.13 (13.22) vs . 54.13 (18.56) -30.00 (-39.29 to -20.70)a,b
RESULTADOS
FIGURA 3. MUDANÇA NA ESCALA NUMÉRICA DE DOR (0 – 10) DURANTE CPM – TASK
(N=60)
Values are given as the median and Q (25-75) (SD). Comparisons among groups comparison was made using the Kruskal-Wallis Test with Dunn's Multiple Comparison Test to identify changes between groups.
Median
Quartile
(25 -75)
P
Median
Quartile
(25 -75)
P
(1) a-tDCS /a-IMS (n= 15)
27.89
(14.83 ; 59.57)
0.56
18.69
(4.47 ; 35.00)
0.58
(2) a-tDCS / s-IMS
(n= 15)
30.15
(6.18 ; 57.43)
19.96
(10.18 ; 42.00)
(3) s-tDCS / a-IMS
(n= 15)
24.95
(13.52 ; 38.68)
21.70
(5.99 ; 50.00)
(4) s-tDCS /s-IMS
(n= 15)
23.87
(11.76 ; 42.69)
18.11
(5.20 ; 49.68)
TABELA 3. COMPARAÇÃO ENTRE NÍVEIS SÉRICOS DE BDNF ENTRE GRUPOS PRÉ E
PÓS TRATAMENTO (N=60)
RESULTADOS
FIGURA 4. CORRELAÇÃO ENTRE NÍVEIS SÉRICOS DE BDNF E LIMIAR DE DOR À
PRESSÃO (N=60)
RESULTADOS
Melhora maior e sustentada da dor
Melhora da capacidade funcional
Reforço do sistema modulatório descendente de dor
As terapias em sequência promoveram efeito sinergístico (priming)
Menor consumo de analgésicos
Níveis de BDNF previram baixos resultados do tratamento no limiar de dor
DISCUSSÃO
Schabrun 2014, Choi 2014, Zhang 2014, DosSantos 2016, Lefaucher 2017, Simão 2014, Zanette 2014.
Processo inflamatório sustentado da OA de joelhos leva ao
enfraquecimento do sistema modulatório descendente da dor.
Ativação reduzida do sistema endógeno de modulação da dor.
IMS: Reforço do sistema inibitório corticoespinhal, cortical e
infra-cortical: ↓PEM, ↓FIC, ↑PSC.
IMS + tDCS: Reforço do sistema inibitório descendente e
homeostase do sistema excitatório. Promove melhora significativa.
CONCLUSÃO
Prof. Dr. Wolnei Caumo
UFRGS/FAMED/PPGCM
HCPA
Alicia Deitos
Aline Brietzke
Daniela Santos
Letícia Angoleri
Mateus Lech
Funcionários CPC e UAMP
Serviço de Fisiatria e Reabilitação –
HCPA
CAPES
CNPq
FAPERGS
