Continuous Repetitive Transcranial Magnetic Stimulation for intractable

Neuropathic Pain

Youichi Saitoh, M.D., Ph.D.Department of Neuromodulation and Neurosurgery

Office for Univeristy-Industry Collaboration,Osaka University

Dec 7, 2012

Rasche et al., Pain, 2006

Electrical motor cortex stimulation; EMCS

Saitoh et al. J Neurosurg 2000Department of Neurosurgery, Osaka University Graduate School of Medicine

EMCS expand to the world from Japan

Efficacy of EMCS on intractable neuropathic pain

Saitoh and Yoshimine, Acta Neurochir Suppl, 2007

Approximately half of the patients satisfy

No large double-blinded clinical trials

Saitoh Y et al, Acta Neurochir, 2007

Repetitive transcranial magnetic stimulation (rTMS)

Eddy currentFigure-8-coil is most popular

curent

Cochrane reviewO’Connell NE et al, 2010Non-invasive brain stimulation techniques for chronic pain

Single doses of high-frequency rTMS of motor cortex may have short-term effects on chronic pain.

Efficacies of cranial electrotherapy stimulation and transcranial direct current stimulation are uncertain.

VS

Multi-centered, Randomized, double-blind, sham-controlled, crossover study

2009 〜 2011

This study was funded by the Japanese Ministry of Health, Labour and Welfare with a Health and Labour Sciences Research Grant.

Randomized, double-blind, sham-controlled, crossover study

Real (5Hz) and sham stimulations are randomized.Double-blind Randomized Crossover StudySpecialist of biological statistics randomized the patients to two

groups.Validation of efficacy and safety of daily rTMS for 2 weeks.

Previous studies were mostly single sessionPrimary endpoint is VAS, secondary is SF-MPQ

Realistic sham is applied.Synchronized cutaneous electrical stimulation is delivered.Hamada M et al, Mov Disord, 23:1524-31, 2008

70 patients

Randomized, double-blind, sham-controlled, crossover study

Seven centersRehabilitation, Hokaido Univ.Neurology, FukushimaNeurosurgery, Nihon Univ.Neurosurgery, Hamamatsu Univ.Neurosurgery, Osaka Univ.Neurology, Kinki Univ.Neurology, Univ. of Occulational

Protocol of sham-controlled crossover study　 Observati

on Intervention Observation

day 　 1 2 3 4 5 6～ 7 8 9 10 11 12 13 ～14 15 16 ～

21 22 23 ～28 29

Examination □ □ □ □ □ □ □ □ □ □ □ □ □ □rTMS 　 ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆

Agreement ○Background ○

MRI/EEG ○Subjective signObjective sign ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○Adverse effect 　 ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

VAS ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○SF-MPQ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

BDI ○ ○ ○ ○ ○ ○PGIC ○ ○ 　 　 　 　 　 ○ 　 　 　 　 　 ○ 　 ○ 　 ○

VAS, Visual analogue scale; SF-MPQ, short form of McGill pain questionnaire; BDI, Beck depression inventry

Trial profileSham firstReal first

Results of short-term effect of VASPrimary endpoint

-2

0

2

4

6

8

10

12Group A (Real) Group A (Sham)

Group B (Real) Group B (Sham)

Day

VA

S re

duct

ion

rate

% (S

EM)

1 2 3 4 5 8 9 10 11 12 1 2 3 4 5 8 9 10 11 12

First period

First week Second week First week Second week

Second period

Results of short-term effect of SF-MPQ Secondary endpoint

0

5

10

15

20

25 Group A (Real) Group A (Sham)

Group B (Real) Group B (Sham)

Day

SF-M

PQ re

duct

ion

rate

% (S

EM)

1 2 3 4 5 8 9 10 11 12 1 2 3 4 5 8 9 10 11 12

First period

First week Second week First week Second week

Second period

1 2 3 4 5 8 9 10 11 12 1 2 3 4 5 8 9 10 11 12

First period

First week Second week First week Second week

Second period

Patient global impression of change (PGIC)

Intervention

Beck depression inventory (BDI)

Intervention

　 　 Number of patients 　 　 　 Number of

respondersMean efficacy

rate (%)　

[95% CI]　 Interaction p

value　 　 　 　 　 　 　Sex 　 　 　 　 　 　 　 　 　 　 　 　　 Male 39 　 　 　 9 23 [ 10.6 - 31.8 ] 0.509

　 Female 22 　 　 　 3 13.6 [ 2.9 - 34.9 ] 　Age 　 　 　 　 　 　 [ 　 - 　 ] 　　 <60 24 　 　 　 6 25 [ 9.8 - 46.7 ] 0.513

　 ≥60 37 　 　 　 6 16.2 [ 6.2 - 32 ] 　Underlying disease 　 　 　 　 　 　 [ 　 - 　 ] 　　 Cerebral lesion 50 　 　 　 10 20 [ 10 - 33.7 ] 1

　 Non-cerebral lesion 11 　 　 　 2 18.2 [ 2.3 - 51.8 ] 　Lesion site 　 　 　 　 　 　 [ 　 - 　 ] 　　 Thalamus 28 　 　 　 3 10.7 [ 2.3 - 28.2 ] 0.14

　 Lenticular nucleus 17 　 　 　 6 35.3 [ 14.2 - 61.7 ] 　　 Others 16 　 　 　 3 18.8 [ 4 - 45.6 ] 　Treated painful region 　 　 　 　 　 [ 　 - 　 ] 　　 Face 6 　 　 　 1 16.7 [ 0.4 - 64.1 ] 0.588

　 Upper limb 32 　 　 　 8 25 [ 11.4 - 43.4 ] 　　 Lower limb 23 　 　 　 3 13 [ 2.7 - 33.6 ] 　Pain laterality 　 　 　 　 　 　 [ 　 - 　 ] 　　 Left 27 　 　 　 6 22.2 [ 8.6 - 42.2 ] 0.407

　 Right 34 　 　 　 11 17.6 [ 6.8 - 34.5 ] 　Previous treatment 　 　 　 　 　 　 [ 　 - 　 ] 　　 Medication alone 43 　 　 　 9 20.9 [ 10 - 36 ] 1

　 Block 12 　 　 　 2 16.7 [ 2.1 - 48.4 ] 　　 Others 6 　 　 　 1 16.7 [ 0 - 64.1 ] 　　 　 　 　 　 　 　 　 　 　 　 　 　 　　 　 　 　 　 　 　 　 　 　 　 　 　 　　 　 　 Efficacy rate (%) 　 　 　　 　 　 　　

Figure 6: Forest plot of subgroup analyses

Short-term efficacy rate (VAS reduction rate subtracting sham of ≥10%) of each subgroup was shown. 95% CIs were calculated by exact binominal method.

0 10 20 30 40 50 60 70 80

Forest Plot of subgroup analyses

Adverse effects

DiscussionThis prospective study shows daily high-frequency rTMS is

transiently effective for pain relief in intractable neuropathic pain patients (70 cases).

There has been no serious adverse effects.The real rTMS, compared with the sham, showed significant

short-term improvements in VAS and SF-MPQ scores without a carry-over effect. The result of PGIC suggested cumulative effect.

More than once a day or continuous rTMS treatment may improve the effect.

In this study, 81% of enrolled patients were post-stroke pain and 60.7 y.o. (mean) which is older than previous studies. Therefore, the effect was mild but significant.

PFC

rTMS

M1

Th

S2

InsPAG

ACCModulate pain recognition

Pain relief

Elicit plastic changes

Cerebral mechanism of pain relief(EMCS, rTMS)

Modulate a pain threshold

Thank you for attention!!