Long-term antalgic effects of repetitive transcranial magnetic stimulation of motor cortex and serum beta-endorphin in patients with phantom pain


Ahmed, M.A.; Mohamed, S.A.; Sayed, D.

Neurological Research 33(9): 953-958

2012


To assess the long-term analgesic effect of repetitive transcranial stimulation (rTMS) on chronic phantom pain using high frequency stimulation and to measure the serum beta-endorphin level pre- and post-rTMS. The study included 27 patients with unilateral amputation; all patients had chronic phantom pain. The patients were classified into two groups. Seventeen patients received 10 minutes real rTMS over the hand area of motor cortex (20 Hz, 10 second trains, intensity 80% of motor threshold) every day for five consecutive days and 10 patients received sham stimulation. Pain was assessed using a visual analogue scale (VAS) and the Leeds assessment of neuropathic symptoms and signs (LANSS) scale, before and after the first, fifth sessions, one and two months after the last session. Quantitative determination of serum beta-endorphin before and after five sessions was measured. There was no significant difference between true and sham groups in the duration of illness, VAS, LANSS scores and resting motor threshold in upper and lower limb amputation at the base line. VAS and LANS scores of the patients who received real rTMS decreased more over the course of the treatment through the different points of follow-up (after five sessions, one and two months) than those who received sham stimulation. Serum beta-endorphin was increased significantly after real stimulation with no changes in patients received shame. Serum beta-endorphin showed no significant correlation to Hamilton depression, anxiety, VAS and LANS scores in true or sham groups before or after five sessions for rTMS. These results confirm that five daily sessions of rTMS over motor cortex can produce long lasting pain relief in patients with phantom pain and it might be related to an elevation of serum beta-endorphin concentration.

Long-term
antalgic
effects
of
repetitive
transcranial
magnetic
stimulation
of
motor
cortex
and
serum
beta-endorphin
in
patients
with
phantom
pain
Mohamed
A
Ahmed',
Sahar
A
Mohamed
2
,
Douaa
Sayed
3
1
Neurology
Department,
Assiut
University
Hospital,
Egypt,
2
Anesthesiology
Department,
3
Clinical
Pathology
Department,
South
Egypt
Cancer
Institute,
Egypt
Objectives:
To
assess
the
long-term
analgesic
effect
of
repetitive
transcranial
stimulation
(rTMS)
on
chronic
phantom
pain using
high
frequency
stimulation
and
to
measure
the
serum
beta-endorphin
level
pre- and
post-rTMS.
Material
and
methods:
The
study
included
27
patients
with
unilateral
amputation;
all
patients
had
chronic
phantom
pain.
The
patients
were
classified
into
two
groups.
Seventeen
patients
received
10
minutes
real
rTMS
over
the
hand
area
of
motor
cortex
(20
Hz,
10
second
trains,
intensity
80%
of
motor
threshold)
every
day
for
five
consecutive
days
and
10
patients
received
sham
stimulation.
Pain
was
assessed
using
a
visual
analogue
scale
(VAS)
and
the
Leeds
assessment
of
neuropathic
symptoms
and
signs
(LANSS)
scale,
before
and
after
the
first,
fifth
sessions,
one
and
two
months
after
the
last
session. Quantitative
determination
of
serum
beta-endorphin
before
and
after
five
sessions
was
measured.
Results:
There
was
no
significant
difference
between
true
and
sham
groups
in
the duration
of
illness,
VAS,
LANSS
scores
and
resting
motor
threshold
in
upper
and
lower
limb
amputation
at
the
base
line.
VAS
and
LANS
scores
of
the
patients
who
received
real
rTMS
decreased
more
over
the
course
of
the
treatment
through
the
different
points
of
follow-up
(after
five
sessions,
one
and
two
months)
than
those
who
received
sham
stimulation.
Serum
beta-endorphin
was
increased
significantly
after
real
stimulation
with
no
changes
in
patients
received
shame.
Serum
beta-endorphin
showed
no
significant
correlation
to
Hamilton
depression,
anxiety,
VAS
and
LANS
scores
in
true
or
sham
groups
before
or
after
five
sessions
for
rTMS.
Conclusion:
These
results
confirm
that
five
daily
sessions
of
rTMS
over
motor
cortex
can
produce
long
lasting
pain
relief
in
patients
with
phantom
pain
and
it
might
be
related
to
an
elevation
of
serum
beta-
endorphin
concentration.
Keywords:
Analgesic
effect,
Beta-endorphin,
Motor
cortex,
rTMs
Introduction
Peripheral,
spinal,
and
cerebral
neuronal
mechanisms
may
generate
and
maintain
phantom
limb
pain,
including
plastic
changes
occurring
in
the
primary
somatosensory
cortex."
Similar
plastic
changes
may
occur
in
the
primary
motor
cortex
(M1),
as
shown
after
nerve
transections
in
animals."
In
humans,
cortical
plastic
changes
could
be
shown
by
using
an
ischemic
nerve
block
as
a
model
for
a
transient
deafferentation,
7
and
studying
the
cortical
representa-
tion
of
proximal
stump
muscles
after
amputation
by
transcranial
magnetic
stimulation
(TMS)
mapping"
or
positron
emission
tomography.
Correspondence
to:
Mohamad
A
Ahmed,
Neurology
Department,
Assiut
University
Hospital,
Assiut,
Egypt.
Email:
yahoo.com
Most
treatments
for
phantom-limb
pain
are
ineffec-
tive
and
do
not
take
account
of
the
mechanisms
underlying
the
production
of
the
pain.
11
A
maximum
benefit
of
about
30%
has
been
reported
from
treat-
ments
such
as
local
anesthesia,
sympathectomy,
dorsal-root
entry-zone
lesions,
cordotomy
and
rhizot-
omy,
neurostimulation
methods,
or
pharmacological
interventions
such
as
anticonvulsants,
barbiturates,
antidepressants,
neuroleptics,
and
muscle
relaxants.
This
proportion
does
not
exceed
the
placebo
effect
reported
in
other
studies.
11
'
12
Significant
analgesic
effects
of
rTMS
have
been
found
in
several
studies
of
patients
with
chronic
pain
of
various
origins.
M1
stimulation
at
high
frequency
was
shown
to
reduce
pain
scores
by
20
to
45%
after
active
stimulation
and
by
less
than
10%
after
sham
©
W.
S.
Maney
&
Son
Ltd
am
DOI
to.1179/17431321311Y.0000000045
Neurological
Research
2011
VOL.
33
NO.
9
953
Ahmed
et
al.
Antalgic
effects
of
repetitive
transcranial
magnetic
stimulation
stimulation.
The
therapeutic
applications
of
rTMS
in
pain
syndromes
are
limited
by
the
short
duration
of
the
induced
effects,
but
prolonged
pain
relief
can
be
obtained
by
repeating
rTMS
sessions
every
day
for
several
weeks.
13
The
mechanism
for
the
analgesic
effect
of
rTMS,
is
that
the
noninvasive
stimulation
can
induce
plastic
changes
in
the
brain,
which
in
turn
corrects
or
modulates
plastic
changes
associated
with
chronic
pain.
Initial
evidence
suggests
that
TMS
affects
central
neurotransmitters
activity
in
other
neurologi-
cal
diseases.
14
'
15
Other
studies
also
indicate
the
possible
role
of
endogenous
opioid
secretions
trig-
gered
by
long-term
MCS.
16
'
17
Beta-endorphin
is
released
into
blood
from
the
pituitary
gland
and
into
spinal
cord
and
brain
from
hypothalamic
neurons.
The
beta-endorphin
that
is
released
into
the
blood
cannot
enter
the
brain
in
large
quantities
because
of
the
blood
brain
barrier.
18
Khedr
et
a1.
19
measured
serum
dopamine
after
repeated
sessions
of
rTMS
as
reflection
of
central
nervous
system
dopamine.
The
present
study
aimed
to
assess
the
long-term
analgesic
effect
of
repetitive
transcra-
nial
stimulation
on
chronic
phantom
pain
using
high
frequency
stimulation,
and
to
measure
the
serum
beta-endorphin
level
pre-
and
post-rTMS
as
an
expectation
of
endogenous
endorphins
in
nervous
system.
Material
and
Methods
Patients
This
study
was
conducted
at
the
Department
of
Neurology
of
Assiut
University
Hospital,
Assiut,
Egypt,
with
participation
of
the
Chronic
Pain
Unit
of
Anesthesiology
Department,
South
Egypt
Cancer
Institute,
Egypt.
The
study
included
27
patients
with
unilateral
amputation,
11
patients
had
upper
limb
amputation
(10
of
them
above
elbow)
and
16
patients
had
blow
knee
amputation.
All
patients
had
chronic
phantom
pain.
Clinically
phantom
pain
was
abnor-
mally
painful
sensation
of
great
intensity
that
they
described
as
burning,
tearing,
or
deep-boring
either
a
spontaneous
or
commonly
evoked
by
trivial
stimuli.
Neurological
examination
revealed
an
increased
threshold
for
pinprick
and
thermal
sensation
in
the
painful
area
in
all
patients
and
a
decrease
in
tactile
sensations
of
varying
degrees
in
some
patients;
all
patients
had
no
motor
deficit.
Studied
patients
had
been
treated
with
various
medications,
including
anticonvulsants,
narcotic
or
non-narcotic
analgesics
and
antidepressants,
without
satisfactory
pain
control.
The
patients
were
classified
into
two
groups.
Seventeen
patients
received
true
rTMS,
the
mean
age
was
52.01
+
12.7
years,
13
(76.5%)
were
males,
the
mean
duration
of
illness
was
33.4±
39.3
months
and
10
patients
received
sham,
the
mean
age
was
53.3±
13.3
years,
6
(60%)
were
males,
the
mean
duration
of
illness
was
31.9
+
21.9
months
with
no
significant
differences
between
the
two
groups.
Patients
with
intracranial
metallic
devices
or
with
pacemakers
or
any
other
device,
as
well
as
those
with
extensive
myocardial
ischemia
and
those
known
to
have
epilepsy,
neurological
or
psychiatric
diseases
were
excluded.
All
patients
participated
in
the
study
after
giving
written
informed
consent
and
the
local
ethical
committee
of
Assiut
University
Hospital
approved
the
procedures.
The
baseline
assessment
consisted
of
a
full
history
and
neurological
examination
followed
by
instruction
in
the
use
of
a
visual
analogue
scale
(VAS).
Each
patient
then
provided
two
VAS
ratings,
and
the
mean
was
taken.
After
this
the
patients
were
assessed
by
the
examiner
using
the
Leeds
assessment
of
neuropathic
symptoms
and
signs
(LANSS)
pain
scale,
which
is
based
on
analysis
of
sensory
description
and
bedside
examination
of
sensory
dysfunction."
Measures
of
VAS
and
LANSS
were
taken
at
each
follow-up
point.
Patients
were
randomly
assigned
to
one
of
the
two
groups,
depending
on
the
day
of
the
week
on
which
they
were
recruited.
One
group
(consisting
of
patients
recruited
on
Saturday
to
Tuesday)
received
real
rTMS
and
the
other
group
(recruited
on
Wednesday
to
Thurs-
day)
received
sham-rTMS.
Preparation
The
patient
sat
in
a
comfortable
chair
and
was
asked
to
relax
as
much
as
possible.
Electromyography
record-
ings
from
the
contralateral
muscle
proximal
to
the
stump
(mainly
deltoid
in
upper
limb
and
Quadriceps
in
lower
limb
amputee)
were
acquired
with
silver—silver
chloride
surface
electrodes,
using
a
muscle
belly-tendon
set-up,
with
a
3
cm
diameter
circular
ground
electrode
placed
on
the
wrist.
A
Dantec
Keypoint
electromyo-
graph
was
used
to
collect
the
signal
(Dantec,
Skovlunde,
Denmark).
Electromyography
parameters
included
a
bandpass
of
20-1000
Hz
and
a
recording
time
window
of
200
ms.
TMS
was
performed
with
a
commercially
available
90
mm
figure-of-eight
coil
connected
to
Mag-Lite
r25
stimulator
(Dantec
Medical,
Skovelund,
Denmark).
Determination
of
resting
motor
threshold
First,
we
determined
the
optimal
scalp
location
from
which
TMS
evoked
motor
potentials
of
greatest
amplitude
in
the
muscle
proximal
to
the
stump.
We
used
constant
suprathreshold
stimulus
intensity
and
moved
the
figure-of-eight
coil
systematically
in
1
cm
steps
to
determine
the
scalp
position
from
where
TMS
evoked
motor
potentials
of
maximum
peak
to
peak
amplitude
in
the
target
muscle.
The
coil
was
positioned
tangentially
to
the
scalp
and
oriented
so
that
the
induced
electrical
currents
would
flow
approximately
perpendicular
to
the
central
sulcus,
at
a
45°
angle
from
954
Neurological
Research
2011
VOL.
33
NO.
9
Ahmed
et
al.
Antalgic
effects
of
repetitive
transcranial
magnetic
stimulation
the
mid-sagittal
line.
21
Single
pulse
TMS
was
then
delivered
to
the
optimal
location
starting
at
supra-
threshold
intensity
and
decreasing
in
steps
of
2%
of
the
stimulator
output.
Relaxation
and
electromyography
signals
were
monitored
for
20
milliseconds
prior
to
stimulation.
The
resting
motor
threshold
was
defined
as
the
minimal
intensity
required
to
elicit
motor
evoked
potentials
of
50
µV
peak
to
peak
amplitude
in
five
out
of
10
consecutive
trials.
22
The
optimal
scalp
location
and
coil
orientation
were
marked
using
a
red
marker
to
reuse
for
daily
rTMS.
Repetitive
transcranial
magnetic
stimulation
Real
rTMS
involved
applying
a
train
of
rTMS
once
per
minute
for
10
minutes.
Each
train
consisted
of
200
pulses
at
20
Hz
and
80%
resting
motor
threshold
(total
duration
of
10
seconds)
applied
through
a
figure-of-eight
coil
over
the
identified
motor
cortical
area
corresponding
to
the
stimulated
stump
muscle
of
the
painful
side.
The
treatment
was
repeated
every
day
for
five
consecutive
days.
Sham-rTMS
was
applied
using
the
same
parameters
but
with
the
coil
elevated
and
angled
away
from
the
head
to
reproduce
some
of
the
subjective
sensation
of
rTMS
and
yet
avoid
induction
of
current
in
the
brain.
23
However,
none
of
the
patients
had
experienced
rTMS
pre-
viously,
they
were
unaware
of
which
stimulation
was
real
and
which
was
sham.
During
the
rTMS,
all
patients
wore
earplugs
to
protect
the
ears
from
the
acoustic
artifact
associated
with
the
discharge
of
the
stimulation
coil.
Sample
collection
and
storage
Two
blood
samples
were
collected
for
each
patient
for
the
assay.
The
first
was
taken
before
the
first
session
of
rTMS
while
the
second
was
taken
1
to
2
hours
after
the
last
session.
The
samples
were
collected
20
to
30
minutes
after
venipuncture
to
avoid
physical
and
psychological
stress
on
the
beta-endor-
phin
concentration.
Hemolytic
and
especially
lipemic
samples
were
not
used
for
the
assay
to
avoid
false
values.
The
serum
samples
were
stored
at
—20°C.
Determination
of
serum
beta
-
endorphin
Beta-endorphin
ELISA
kit
(Phoenix
Pharmaceuticals,
Inc.
Burlingame,
CA,
USA)
was
used
in
the
determi-
nation.
Enzyme
linked
immunoassay
was
performed
as
manufacturer
instructions.
The
calibration
curve
from
which
the
concentra-
tion
of
beta-endorphin
in
the
samples
was
obtained
by
plotting
the
extinction
values
measured
for
the
six
standards
(linear,
y
axis)
against
the
corresponding
concentrations
(logarithmic,
x
axis).
The
results
for
unknown
can
be
calculated
using
the
following
curve-
fitting
technique
four-parameter
logistic.
Follow
-
up
Patients
were
followed
up
after
the
first,
fifth
rTMS
session,
1
and
2
months
after
the
last
session,
using
the
VAS
and
LANSS
scales.
The
second
author
evaluated
these
measures
blindly,
without
knowing
the
type
of
rTMS.
Data
analysis
Pain
level
was
assessed
at
baseline,
after
the
first,
fifth
rTMS
session,
1
and
2
months
after
the
last
session
using
the
VAS
and
LANSS
scales.
Values
for
both
patient
groups
(true
and
sham)
and
each
rating
scale
(VAS
and
LANSS)
were
analyzed
in
separate
two
factor
analysis
of
variance
with
'time after
start
of
treatment'
and
`rTMS'
as
main
factors.
The
Greenhouse—Geisser
correction
of
degrees
of
freedom
was
used
when
necessary
to
correct
non-sphericity
of
data.
The
percentage
of
the
pain
level
was
calculated
from
the
VAS
score
measured
before
and
after
the
rTMS
sessions,
both
real
and
sham,
by
the
following
equation:
(post-rTMS—pre-rTMS
pain
scores)
x
100/pre-rTMS
pain
score
Results
There
was
no
significant
difference
between
true
and
sham
groups
in
the
duration
of
illness,
VAS,
LANSS
scores
and
resting
motor
threshold
in
upper
and
lower
limb
amputation
at
the
base
line.
Demographic
and
clinical
results
are
presented
in
Table
1.
Figure
1
shows
that
the
VAS
score
of
the
patients
who
received
real
rTMS
decreased
significantly
all
over
the
course
of
the
treatment
through
the
different
points
of
follow-up
(after
5
sessions,
1
and
2
months)
than
those
who
received
sham
rTMS.
This
was
confirmed
in
a
two
factor
repeated
measures
analysis
of
variance
sepa-
rately
in
each
group
of
patients
with
'time
of
assessment'
and
`rTMS'
as
main
factors
(P=0.001
in
real
versus
0.69
in
sham
rTMs).
The
same
results
were
reported
in
LANSS
rating
scale
(Fig.
2).
There
was
a
significant
decrease
in
pain
ratings
at
time
points
(5
sessions,
1
and
2
months
follow-up)
after
real
rTMS
compared
with
baseline
(P=0.001),
but
no
significant
change
in
sham
patients.
There
were
no
significant
Table
1
Demographic
and
clinical
data
of
the
true
and
sham
groups
True
(n=17)
Sham
(n=10)
Age
(years)
52.01+12.7
53.3+13.3
Duration
of
illness
(month)
33.4+39.3
31.9+21.9
Sex
Male
13
(76.5%)
6
(60%)
Female
4
(23.5%)
4
(40%)
Site
of
amputation
Upper
limb
7
(41.2%)
4
(40%)
Lower
limb
10
(58.8%)
6
(60%)
Cause
9
(52.9%)
4
(40%)
Traumatic
2
(11.8%)
4
(40%)
Ischemic
6
(35.3%)
2
(20%)
Diabetic
17
(100%)
10
(100%)
Phantom
pain
Resting
motor
threshold
Upper
limb
38.5+5.1
(7)
40.5+3.1(4)
Lower
limb
64.8+17.38
(10)
73.1+19.4
(6)
Neurological
Research
2011
voL.
33
NO.
9
955
Ahmed
et
al.
Antalgic
effects
of
repetitive
transcranial
magnetic
stimulation
Effect
of
rTMS
on
VAS
scale
-8-
REA
L
GROUP
-II-SHAM
GROUP
10
9
-
s
7
5
-
4
3
2
-
1
-
o
BEFORE
AFTER
I
AFTER
5
AFTER
1
AFTER
2
SESSION
SESSION
SESSIONS
MONTH
MONTH
Figure
1
Effect
of
rTMS
on
VAS
scale.
Effect
of
rTMS
on
LANSS
scale
REAL
GROUP
25
-M-SHAM
GROUP
20
15
10
-
5
0
BEFORE
AFTER
1
AFTER
5
AFTER
1
AFTER
2
SESSION SESSION
SESSIONS
MONTH MONTH
Figure
2
Effect
of
rTMS
on
LANS
scale.
changes
in
VAS
and
LANS
rating
scales
after
the
first
session
in
real
and
sham
groups
(Table
2).
The
percentage
reduction
in
VAS
in
the
real
rTMS
group
decreased
by
55%
at
the
end
of
the
fifth
treatment
session
and
was
still
reduced
by
52%
1
month
later
and
39%
after
2
months
follow-up
compared
with
baseline
measures.
The
percentage
was
higher
in
patients
with
upper
limb
phantom
pain
(55,
56,
and
60%
respectively)
compared
to
patients
with
lower
limb
phantom
pain
(55,
51,
and
24%
respectively).
In
contrast,
pain
ratings
in
the
sham
group
declined
only
by
7%
after
5
sessions
and
2%
after
1
and
2
month
follow-up.
Serum
beta-endorphin
of
normal
volunteers
(n=10)
was
2.90
+
1.47
ng/ml
(normal
value
from
0
to
100
ng/ml).
Serum
beta-endorphin
of
the
patients
were
very
low
(0.98
±
50
in
true
group
and
1.07
±
0.58
in
sham
group)
in
comparison
to
normal
volunteers.
Beta-endorphin
was
measured
1
to
2
hours
after
five
sessions
of
rTMS,
it
was
increased
significantly
after
real
stimulation
but
patients
received
shame
rTMS
showed
no
significant
change
(Fig.
3,
Table
3).
Hamilton
depression
and
anxiety
scores
showed
significant
decrease
in
patients
received
real
rTMS
but
no
changes
were
observed
in
those
with
shame
sessions
(Table
3).
Spearman's
correlation
showed
that
duration
of
illness
had
significant
positive
correlation
to
serum
beta-endorphin
before
rTMS
(r=0.54,
P=0.02)
and
negative
correlation
to
resting
motor
threshold
(r
=
-0.65,
P=0.004).
Serum
beta-
endorphin
showed
no
significant
correlation
to
Hamilton
depression,
anxiety,
VAS
and
LANS
scores
in
true
or
sham
groups
before
or
after
five
sessions
of
rTMS.
Discussion
The
results
in
the
present
work
confirmed
that,
20
Hz
stimulation
in
the
motor
cortex
contralateral
to
amputated
limb
had
long-term
analgesic
effect
at
the
end
of
5
sessions
and
1,
2
month
follow-up.
The
effect
was
reported
in
upper
limb
as
well
as
lower
limb
amputee.
Pain
reduction
in
VAS
in
the
real
rTMS
group
decreased
by
55%
at
the
end
of
the
fifth
treatment
session
and
was
still
reduced
after
1
and
2
month
follow-up.
The
percentage
was
high
in
patients
with
upper
limb
phantom
pain
compared
to
patients
with
lower
limb
pain.
To
our
knowledge,
only
a
few
authors
studied
the
effect
of
TMS
on
phantom
pain,
Rollnik
and
Pridmore's
24
protocol
including
only
one
patient
with
phantom
pain
and
Irlbacher
et
al:S
25
study
included
14
patients
with
phantom
pain.
Both
reported
significant
reduction
in
pain
score
and
the
second
author
reported
no
long-
term
analgesic
effect
of
rTMS
as
they
used
low
stimulation
frequency
(1
and
5
Hz)
in
comparison
to
the
present
work
as
we
used
20
Hz
on
large
number
of
patients
(27
patients).
Our
results
were
parallel
to
others
studies
on
different
types
of
pain
other
than
phantom
pain.
Lefaucheur
et
a1.
26
demonstrated
that
rTMS
was able
to
relieve
neuropathic
pain
when
Table
2
VAS
and
LANS
scores
before
and
after
rTMS
sessions
True
(Mean
+SD)
P
value
Shame
(Mean
+SD)
P
value
VAS
Before
sessions
7.4+1.3
7.60+0.84
After
1
session
7.1+2.1
0.40
7.80
+
0.91
0.59
After
5
sessions
3.4+1.2
0.001
7.40+0.84
0.59
After
1
month
3.4+1.7
0.001
7.30+0.82
0.46
After
2
months
4.5
+
2.2
0.001
7.60+0.96
1.0
LANS
Before
sessions
17.2±
3.7
18.10+1.9
After
1
session
16.8+3.4
0.38
17.30+1.9
0.11
After
5
sessions
8.4
+
3.7
0.001
17.8+2.3
0.49
After
1
month
7.6
+
2.7
0.001
17.4±
2.2
0.19
After
2
months
9.5
+
3.7
0.001
16.8+1.7
0.04
Note:
P
value
was
between
each
point
of
follow-up
and
base
line
assessment
of
VAS
and
LANS
scores
before
sessions.
956
Neurological
Research
2011
voL.
33
NO.
9
Ahmed
et
al.
Antalgic
effects
of
repetitive
transcranial
magnetic
stimulation
Effect
of
rTMS
on
serum
endorphine
level
.M
PRE
SESSIONS
POST
SESSIONS
4.5
4
3.5
3
2.S
endorphin
2
level
(ngm)
0.5
a
REAL
SHAM
patient
groups
Figure
3
Effect
of
rTMS
on
serum
beta-endorphin
level.
administered
over
M1
at
10
Hz
but
not
at
0.5
Hz.
Andre-Obadia
et
al.
27
also
showed
that
rTMS
provided
better
alleviation
of
pain
at
20
Hz
than
at
1
Hz
and
Saitoh
et
a1.
28
found
that
10-Hz
rTMS
was
more
effective
than
5-Hz
rTMS,
whereas
1-Hz
rTMS
did
not
produce
significant
effects.
In
the
present
study.
there
were
no
significant
effects
on
VAS
or
LANS
scores
after
the
first
session
and
the
effects
persist
for
2
months
after
the
end
of
sessions
due
to
cumulative
effects
lasting
for
at
least
2
months
beyond
the
time
of
stimulation
after
repeated
TMS.
The
same
results
were
reported
by
Lefaucheur
et
a1.,
26
Khedr
et
al.,
29
and
Passard
et
aL
Lefaucheur
et
al.
31
also
concluded
that
rTMS
could
not
be
considered
as
a
therapeutic
method
for
neuropathic
pain
except
if
the
sessions
of
stimulation
were
repeated
for
several
days
or
weeks.
Analgesic
effects
in
the
present
work
occurred
in
all
patients
including
eleven
patient
with
upper
limb
and
16
patients
with
lower
limbs
phantom
pain
treated
by
real
rTMS.
The
pain
reduction
was
higher
in
patients
with
upper
limb
amputee
in
contrast
to
the
patients
with
lower
limb
amputee.
Therefore,
analgesic
effect
of
rTMS
may
act
on
neuronal
networks
by
modulat-
ing
neural
activities
not
only
in
the
stimulated
area,
but
also
in
remote
regions
that
are
interconnected
to
the
site
of
stimulation.
This
was
proved
by
Garcia-
Larrea
and
Peyron,
32
as
they
found
increase
in
the
activity
of
neural
structures
implicated
in
pain
pro-
cessing
as
thalamus,
anterior
insula,
periaqueductal
gray
matter,
and
upper
brainstem
after
treatment
by
epidural
MCS
using
positron
emission
tomography.
The
mechanisms
underlying
the
analgesic
effects
elicited
by
transcranial
cortical
stimulation
of
motor
cortex
are
not
fully
understood
yet
and
the
exact
nature
of
the
involved
pathways
remains
hypothe-
tical.
Raij
et
a/.
33
suggested
that
in
chronic
pain
there
was
defective
inhibition
of
M1
lead
to
pain
percep-
tion
so
20
Hz
rTMS
restored
these
defective
mechan-
ism
and
analgesia.
Others
reported
that
rTMS
may
increase
central
nervous
system
opioids,
Maarrawi
et
a1.
16
reported
that
motor
cortex
stimulation
(MCS)
may
induce
release
of
endogenous
opioids
in
brain
structures
involved
in
the
processing
of
acute
and
chronic
pain.
Amassian
et
a1.
34
suggested
that
analgesic
effects
of
rTMS
in
phantom
pain
were
delivered
by
increase
in
the
endogenous
beta-endor-
phin
release.
T6pper
et
a1.
35
found
that
opiate
antagonist
naloxone
abolished
the
rTMS-induced
pain
relief
which
was
taken
as
evidence
that
the
analgesic
effect
of
rTMS
acted
via
the
release
of
endorphins.
Borckardt
et
al.36'37
also
found
that
a
single
session
of
high-frequency
rTMS
applied
immediately
after
gastric
bypass
surgery
at
10
Hz
over
the
left
DLPFC
for
a
total
of
4000
pulses
was
associated
with
a
40%
reduction
in
total
morphine
use
during
the
first
2
days
after
surgery.
This
redu-
ction
corresponded
to
the
effect
of
active
rTMS
minus
that
of
sham
stimulation.
In
the
present
work,
we
measured
beta-endorphin
in
serum
before
and
after
rTMS
and
in
volunteer
group
not
complaining
from
neuropathic
pain
as
a
marker
to
central
nervous
system
beta-endorphin.
We
found
that
beta-endorphin
in
the
serum
was
low
in
patients
with
phantom
limb
pain
as
compared
to
normal
volunteers
which
explain
the
persistence
of
pain
after
amputation.
After
true
rTMS
the
serum
level
of
beta-endorphin
was
markedly
increased
in
comparison
to
the
level
before
rTMS.
In
spite
of
the
increase
in
the
serum
beta-endorphin,
the
level
was
not
correlated
to
improvement
in
pain
as
measured
by
VAS
and
LANS
score,
improvement
in
Hamilton
depression
and
anxiety
score
after
five
sessions.
This
item
can
be
re-investigated
later
in
a
larger
study
than
the
present
one.
It
seems
possible
that
some
of
the
clinical
improve-
ment
in
patients
following
rTMS
may
have
been
due
to
changes
in
cerebral
beta-endorphin,
with
increases
in
beta-endorphin
causing
improvement
in
pain
score.
Unfortunately,
since
we
were
only
able
to
measure
beta-
endorphin
concentrations
at
a
single
time
point
after
the
last
rTMS
treatment,
we
cannot
say
whether
the
serum
Table
3
Serum
beta-endorphin,
Hamilton
depression
and
Hamilton
anxiety
before
and
after
rTMS
sessions
Before
(Mean
+SD)
After
(Mean
+SD)
P
value
True
Beta-endorphin
(ng/ml)
0.98+0.50
4.5+2.2
0.001
Hamilton
depression
19.5+6.7
10.41+
4.6
0.0001
Hamilton
anxiety
15.8+3.4
9.58+2.9
0.0001
Shame
Beta-endorphin
(ng/ml)
1.07+0.58
1.2+0.59
0.33
Hamilton
depression
17.10+1.59
15.41+
2.4
0.07
Hamilton
anxiety
15.8+1.68
16.20+1.54
0.39
Neurological
Research
2011
VOL.
33
NO.
9
957
Ahmed
et
al.
Antalgic
effects
of
repetitive
transcranial
magnetic
stimulation
increase
was
sustained
for
as
long
as
the
clinical
improvement,
which
in
the
present
cases
persist
for
at
least
2
month
after
the
end
of
sessions.
Thus,
it
is
possible
that
the
sustained
clinical
improvement
could
not
only
related
to
changes
in
beta-endorphin
levels.
Nevertheless,
our
measures
of
beta-endorphin
were
taken
1
to
2
hours
after
rTMS,
so
that
we
think
that
the
effect
may
last
for
some
time
after
the
end
of
stimulation.
Conclusion
From
this
study,
we
can
consider
that
rTMS
for
5
consecutive
days
at
high
frequency
had
long-term
pain
relieve
for
at
least
2
months
after
the
last
session.
Serum
beta-endorphin
level
could
be
con-
sidered
as
evidence
that,
rTMS
can
increase
the
central
nervous
system
endorphins.
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Neurological
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2011
VOL.
33
NO.
9