Special Report

10.1586/14737175.7.11.1485 2007 FutureDrugsLtd ISSN 1473-7175 1485 www.future - drugs.c om

Central pain syndrome: elucidation
of genesis and treatment
S Canavero

and V Bonicalzi

Author for correspondence

Turin Advanced Neuromodulation
Group (Tang), CsoEinaudi 2,
10128 Torino, Italy
Tel.: +39 34 9471 7819
sercan@inwind.it
KEYORDS:
central pain, leukotomy,
motor cortex stimulation,
neuromodulation
Ce ntra l pa in (CP), na me ly, pa in or a llie d symptoms tha t follow da ma ge to the CNS, ha s
rema ined a n obscure neurologica l syndrome with no expla na tion or effective trea tment
sinc e Edingers de scription in 1891. Onc e be lieved to be ra re, CP is now known to a ffect
severa l millions of pe ople worldwide , ma king it a t le a st a s fre quent a s, for exa mple ,
Pa rkinsons disea se. It follows such common entities a s stroke, spina l c ord injury a nd
multiple scle rosis, but a lso ma ny other c onditions, including ne urosurgic a l proc e dure s on
the bra in a nd spine. A disturba nce of tha la mocortica l tra nsmission is now a cknowledged
to be the ma in engine of CP. When drugs fa il, neuromodula tion, both electrica l a nd
chemica l, provide relief to ma ny drug nonresponders. A sma ll stereota ctic lesion deep in
the subpa rie ta l white ma tter promise s c omple te re lie f, without the rava ges of
ne uroa bla tion a s pe rformed wide ly in the pa st.
Expert Rev. Neurotherapeutics7(11), 14851497 (2007)
Historic a l note
In 1888, Frau R, having agonized with terrible
pains for 2 years, committed suicide; not even
opium could relieve her pains, which followed
cerebral infarction. By studying this case, in
1891, Dr Edinger, a doctor working in Frank-
furt-am-Mein, Germany, published his seminal
paper in which he hypothesized the existence
of centrally arising pains [1,2]. The concept that
pain could be released independently of
peripheral nociceptive stimulation was born.
Actually, patients suffering central pain (CP)
had already been described by other authors,
both in western and eastern sources, at least
since the early 1800s; nonetheless, nobody
actually intuited that brain damage alone could
trigger spontaneous, unrelenting pain [1]. In
1938, Riddoch published his three-part review
of CP in Lancet, establishing it as a definite
nosological entity [3]. By that time, it was clear
that CP could follow brain damage at several
levels (cortex, subcortex, thalamus and brain-
stem), but also spinal cord injury (SCI; so-
called paraplegic pain), as amply noted during
World War I [1].
In 1906, Dejerine and Roussy described the
so-called thalamic syndrome, in which, among
other symptoms and signs due to thalamic
stroke, was pain [4]. A few years later, the schol-
arly paper by Head and Holmes clearly defined
the sensory deficits that characterize CP in an
unparalleled description that has not been
surpassed to this day [5]. Unfortunately, focus
on the thalamus sidelined the cortex and other
brain areas and for the best part of the 20th
century CP was considered to be mainly due
to thalamic stroke. Only with the advent of
CT scans (1973) and MRI (1981), it became
clear that pure thalamic lesions are not the
primary triggers [1].
Finally, during the 1990s, a series of epide-
miological studies found CP to be a major,
under-recognized entity, a fact underscored by
a steep increase in the number of articles
appearing in the literature.
De finition & e pide miology
CP is, in fact, an all-encompassing term that
defines pain, but also dysesthesias, paresthesias
and, as recently realized, pruritus [6], initiated
by a CNS lesion impinging on or interfering
with the spinothalamic tract enroute to the
parietal somatosensory areas, in other words,
the path responsible for conduction of nocice-
ptive and thermal stimuli [1]. The anatomic
basis of CP was highlighted in a major work
CONTENTS
Historica l note
Definition & e pide miology
Clinic a l fea ture s &
dia gnostic eva lua tion
Na tura l history
Ge nesis of c e ntra l pa in
Expert commenta ry on
the ra py
Five- yea r view
Informa tion re sourc e s
Fina ncia l & competing
inte rests disclosure
Key issue s
References
Affilia tions
For re print orde rs, ple a se c onta c t re prints@future - drugs.c om
Ca na ve ro & Bonic a lzi
1486 Expert Rev. Neurotherapeutics7(11), (2007)
published in 1969 [7] and was later confirmed by electrophysio-
logical studies employing laser-evoked potentials, which specifi-
cally explore the pain and temperature conducting pathway in
the CNS [1].
Several terms have been attached to CP. Besides thalamic
pain, pseudothalamic pain has been used to define pain due to
suprathalamic lesions, while anesthesia dolorosa has also been
referred to pain following neurosurgical-induced deafferenta-
tion. Dysesthetic pain is another popular term. CP after spinal
injury has been referred to as, among many others, paraplegic
pain or remote pain (as opposed to end-zone pain). All these
terms must be discarded in favor of the much more descriptive
terminology of CP of brain or brainstem origin (as seen in
medullary stroke, i.e., Wallenbergs syndrome) and CP of cord
origin [1].
Long considered to be a neurological rarity, based on sheer
opinion and poor epidemiological observations, we now know
that no less than 10% of all CNS strokes (both ischemic and
hemorrhagic) [8,9], at least 2025% of SCIs, including syringo-
myelia [10], 18% of patients with multiple sclerosis (MS) [11],
perhaps 2% of all cancer patients [12] and an undefined number
of patients with other neurological conditions suffer CP, thus
running in the millions worldwide [1]. In the USA alone, no less
than 600,000 patients suffer CP [1], ten-times more than previ-
ous estimates. Males are generally more represented, in older
age in the case of stroke, in younger age after SCI, with the
exception of MS, which predominantly affects females. An
often unrecognized cause of CP is iatrogenic lesions: CP may
be a complication of neurosurgical procedures both on the
spine and the brain, ranging from disc ablation at dorsal levels
to tumor excision in the parietal lobe, brainstem and cord;
unfortunately, the low awareness of this possibility delays effec-
tive treatment in many patients [1]. Conversely, the paradox of
neurosurgical pain-relieving procedures (e.g., thalamotomies,
mesencephalotomies and cordotomies) triggering new pain, in
other words, CP, is a well recognized fact [7].
Approximately 1% of all epileptic patients suffer painful fits
at least once: we consider this a CP-allied condition, since
there is no actual damage to the parietal projection of the spi-
nothalamic tract. Nonetheless, the end cells of this pathway are
likely involved [1]. For a long time, dysesthetic pain as reported
by some patients with Parkinsons disease has been considered
a form of CP, but recent studies do not confirm this view [13].
Clinic a l fe a ture s & dia gnostic eva lua tion
CP comes in three components [14]:
A constant, spontaneous pain (which may be described as
aching, burning, pricking, lacerating or cramping), dysesthe-
sias, paresthesias pruritus or combinations thereof. Typically,
more than one kind of pain is experienced in 99% of the
patients and cord CP and MS-associated CP tend to be more
dysesthetic [15];
A spontaneous, intermittent, generally lancinating, pain,
which is experienced by approximately 1020% of the cases;
Evoked pain, experienced by approximately two-thirds of the
patients (rarely it can be the only presenting symptom).
In the latter cases, a nonpainful or only mildly painful stimu-
lus is felt as painful or burning (allodynia) or very painful
(hyperalgesia or hyperpathia if it lasts beyond stimulation).
Evoked pain, just like in peripheral neuropathic pain, can be
elicited by mechanical (static or dynamic) or thermal (cold
more than heat) stimuli. In cases described as hyperpathic, pain
is usually unbearable and evokes violent emotional and defen-
sive reactions; characterized by late onset and poor localization,
it generally irradiates from the stimulated point to the entire
half of the body and persists for an unusually long time after
stimulation has ceased. Evoked pain and intermittent shooting
pains can hinder daily activities, as innocuous maneuvers can
trigger fits of intolerable pain. Patients may have to wear a glove
when the hand is most affected. All these anomalous sensations
are referred inside a larger area of sensory loss or hypesthesia, on
the side of the body contralateral to the damage. Pain may be
felt superficially, deep or both. Symptoms may be focal
(hand/arm, hemichest, foot and/or leg) or affect half the body
as generally seen after thalamic and cortical lesions or one side
of the face ipsilaterally and the rest of the hemisoma contralat-
erally (Wallenbergs syndrome), following brainstem injury. CP
after SCI (both complete and incomplete) may involve the
entire body region below the level of injury, but usually is more
intense in the sacral dermatomes, buttocks, genitalia and the
feet. Signs of dystrophy in the affected area may be observed in
some CP patients [1,14].
The intensity of the pain varies from mild, unpleasant
tingling to one of the most agonizing torments known to
humans. CP greatly impairs quality of life, interfering with
sleep patternsand driving some to suicide. Its highly unpleasant
quality disablespatientseven when intensity islow [1,14].
Diagnosis of CP is rather straightforward when a patient
laments pain or other abnormal sensations after CNS injury [1].
The neurological examination usually reveals areas of hypo-
anesthesia to thermal stimuli and pinch. These areas must be
assessed clinically with cold (e.g., an ice cube) and warm stim-
uli, and pinprick. Frequently, evoked pain will be elicited. In
the evaluation of the single patient, pain scales can be
employed, but these are most useful in the research setting.
Owing to its clinical features, which can be mistaken for
peripheral neuropathic pain (e.g., diabetic neuropathy), all
patients must be assessed neuroradiologically and neurophysio-
logically; sensory neuropathies must be excluded. Once sus-
pected, MRI is the exam of choice in the evaluation of CP; a
lesion (ischemic or hemorrhagic lesion, tumor or demyelinating
plaque) is usually seen along the spinothalamic pathway. Laser-
evoked potentials confirm damage of C/A -fibers. Shoul-
derhand pain, which frequently accompanies stroke, is not CP,
but nociceptive pain. Pain caused by muscle cramping or dysto-
nia owing to abnormal tone, posture or muscle excitability is
often seen after CNS damage, and this must be differentiated
from CP [1].
Ce ntra l pa in syndrome : e luc ida tion of ge ne sis a nd tre a tme nt
www.future-drugs.com 1487
Na tura l history
CP generally starts days, weeks or months after the CNS
insult, but may present suddenly or take 1 or more years to
develop [1]; when the delay is in the 1-year range after SCI, a
syrinx may be found on MRI [15]. Once set in, CP remains
with the patient for their lifetime in the vast majority of the
cases. It may fluctuate during the day, depending on such fac-
tors as stress, weather changes, effort and others. Rest and dis-
traction may lessen CP. Unlike brain CP, which usually tends
not to change significantly, except in degree, over time, cord
CP may change remarkably over the years:
it may increase in severity for several years
and even change in distribution and qual-
ity, sometimes dramatically in several
cases [1,15].
Careful studies reveal that CP may
completely and suddenly regress after
removal of the inciting lesion in some
patients [1618]. Similarly, a further stroke
along the parietothalamic axis may abol-
ish the pain [1,19]. These observations
have pathophysiological consequences
(see later).
Ge ne sis of c e ntra l pa in
Scores of different theories have been
proposed to explain CP, both in the past
and recently (FIGURE 1) [1]. For a long time,
the thalamus has played a starring role in
most of them. Animal studies over the
last 20 years have not added to the field,
for the simple reason that brain structure
and neurochemistry differ significantly in
the human (for a discussion see [1]). In
the end, a theory in biomedicine is good
if it leads to therapeutic advances. In this
sense, most theories failed.
The highly popular view that both cen-
tral and peripheral neuropathic pain can
be understood inside the framework of so-
called deafferentation pain [14] has never
made it into international classifications
and, although sharing similar pain
descriptors, differences between them are
so numerous to nullify a pathophysiologi-
cal utility of such grouping. For instance,
while brachial plexus avulsion pain
responds well to standard dorsal root
entry zone (DREZ) lesions, CP of cord
origin does not; similarly, thalamic stimu-
lation and thalamic surgical lesions are by
far more effective for peripheral neuro-
pathic pain than CP [1]. Subhypnotic pro-
pofol can relieve CP, but only rarely
peripheral neuropathic pain [20].
In recent years, it has become clear that CP must be under-
stood inside a framework that includes both the thalamus and
the sensory (SI and perhaps SII) cortex [19,21]. In particular, it is
a derangement of the oscillatory pattern inside the sensory cor-
ticothalamocortical loop that best explains the pathophysiology
of CP (dynamic reverberation theory of CP) [19].
In-depth recordings in the patients brains pointed to several
anomalies in the brainstem, thalamus and cortex [1,14]. In
particular, hyperactivity in the form of bursting activity in the
thalamus, both in sensory and aspecific nuclei, has been
Figure 1. Description of the main players in the genesis of central pain. The large arrow pointing
downward towardsthe thalamicnuclei isthe large descending corticothalamicprojection responsible for
maintaining central pain. Subparietal leucotomy/capsulotomytargetsthisprojection.
Vim
Vc
Pulvinar
TRN
CL
GABA interneurons
Spinothalamic tract
Spinoreticular tract
Medial lemniscus
Reticular
formation
Neuromodulatory
brainstem
influences
SI-MI
Ca na ve ro & Bonic a lzi
1488 Expert Rev. Neurotherapeutics7(11), (2007)
considered a marker of a local dysrhythmia [21,22], but this has
been challenged, as bursting is a modality of transmission of the
normal brain [23]. Conversely, a disturbance in neural patterns
of activity applies both to CP and also many other neurologic
disorders, including Parkinsons disease [24].
Another popular theory emphasizes neuroplastic changes in
the CNS following deafferentation [1,14]. Entrenched neuro-
plasticity, spanning from changes in brain maps to sensitiza-
tion of central structures, has been put forth to explain chro-
nicity [1,14], but sudden resolution of CP after extirpation of
inciting lesions [25] or a further stroke [19] clearly suggests that
plasticity cannot underlie constant pain: both would be revers-
ible in such circumstances [18]. Moreover, careful studies by
Taskers group reveal major differences between what occurs in
the human patient and the experimental animal in terms of
plastic changes [26].
Importantly, CP has been cancelled by lesions interrupting
the thalamocortical loop in the subparietal corona radiata and
internal capsule [1,19]. Careful analysis of such cases reveals
that it is the much larger descending arm of the thalamocorti-
cal loop that is key to maintaining CP over time [1,19]. A role
in feeding the loop comes from hyperactive reticular cells
spread along the spinotruncothalamic axis, whose destruction
may help allay CP [9,27]: this has been highlighted by studies
dealing with mesencephalic reticulotomy [28] and extended
DREZ-tomies [29]. The difference between subparietal lesions
and these latter lesions lies in the rate of disappearance of CP:
sudden versus gradual.
Hyperexcitation of the spinothalamic pathway by the
reticulothalamic system, which in turn is modulated by the
medial lemniscus, is supported by a recent report [30].
Neuroimaging studies with such techniques as SPECT, PET,
functional MRI and others have provided valuable data. Unfor-
tunately, most of them focused on studying evoked pains,
which, as stated, are not key to CP (reviewed in [1]). Studies
investigating the spontaneous component with drug dissection,
although few, have confirmed the role of both the sensory cor-
tex and thalamus [25,3133], while evoked pains elicit different,
wider patterns of neural activity (particularly in prefrontal
areas) [34]. A recent study adopted this view: the evidence of
blood flow, stimulation, and lesion studies forcefully make the
case that (thalamic primary sensory nucleus) ventral caudal
nucleus and sensorimotor cortex are involved in poststroke
central pain (CPSP) [35].
Data from Taskers group also support the view that the gen-
erator of ongoing CP can be shifted to the healthy hemisphere
[36], thus explaining cases of CP after massive destruction of one
thalamus or sensory cortex [19,33]. Clinical observations also
support the possibility for a unilateral CNS lesion to trigger
bilateral CP [3739].
It has been proposed that a certain quota of people may be
genetically predisposed to develop CP [1]. In fact, a lesion any-
where along the spinothalamocortical pathway only triggers CP
in a minority of patients, while sparing most others [14]. Thus,
spinothalamocortical damage is necessary, but not sufficient,
for CP to arise [1,27,34]. In particular, there is a suggestion that
differential sparing of the lemniscal system as compared with
the spinothalamic system may trigger dysesthetic pain [15].
Neuropharmacological data with GABA agonists in human
patients point to a specific derangement of GABA transmis-
sion at the basis of CP [40]. It is surmised that CNS damage in
these cases triggers an acute GABA loss that unbalances the
oscillatory pattern along the thalamocortical loop responsible
for conscious sensory processing, starting in the somatosensory
cortex [1].
In this context, anomalies seen in the cingular and temporal
areas are unspecific findings present in most chronic pain
patients and not the basis of CP. According to Craig, CP
would be subtended by a hyperactive spinothalamocingular
pathway after selective damage to a specific spinothalamo(ven-
tral medial posterior nucleus [VMpo])insular pathway [41]. It
is worth recalling how this thermosensory disinhibition
hypothesis [41] not only has been completely disproven [1] on
clinical and neurophysiological grounds, but also its anatomic
foundations have been totally refuted. In the words of Jones:
The construction does not stand up to critical examina-
tion The VMpo is like one of those religious apparitions
that appear to few but become believed by many (a) dogma
that rests upon the faith of conviction rather than upon docu-
mented evidenceevidence of never having spoken to a
patient with chronic pain [42].
On the other hand, the different components of evoked pain
most likely recognize different pathophysiological mechanisms,
such as thermal versus mechanical allodynia [1,34,43]. Central
sensitization would play a major role in the genesis of these
pains [1,14,43].
The sympathetic nervous system plays no role whatsoever in
the genesis or sustenance of CP [1,4446].
Expe rt c omme nta ry on the ra py
CP is best understood as a cancer of the spirit, which nibbles
away each day at the patients quality of life, until severe disrup-
tion in daily living inexorably sets in. Thus, it is of the utmost
importance that, unlike what happens for most patients, valua-
ble time is not lost trying a smorgasbord of drugs, which are
often useless. If a trial of oral pharmacotherapy produces no
benefit within 6 months, neuromodulation must be the next
option, without further delay.
Drug therapy
In recent years, the choice of drugs has become more evidence
based, owing to the effort of a handful of groups around the
world interested in CP. TABLE1 lists oral drugs submitted to con-
trolled studies. Unfortunately, all such studies suffer from too
short a follow-up and low powering; on the other hand, they
are the best evidence upon which to base recommendations.
Several effective agents have been identified, but many are not
suitable for oral intake. Parenteral drugs, while not useful for
chronic therapy, nonetheless helped elucidate CP mechanisms
(TABLE 2) [40]. Lamotrigine and amitriptyline are the only oral
Ce ntra l pa in syndrome : e luc ida tion of ge ne sis a nd tre a tme nt
www.future-drugs.com 1489
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n
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e
s
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s

[
N
N
T
:
1
2
;

9
5
%

C
I
:

2

]
[
6
5
]
C
a
r
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s

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t

a
l
.

S
C
I

(
2
6
,

t
r
a
n
s
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t
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n

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n
e

p
a
i
n
:

6
)
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o
u
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d
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l
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f
f
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b
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w
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M
Y

a
n
d

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e
n
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e

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e
s
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t
e

(
a
c
t
i
v
e

p
l
a
c
e
b
o
)
[
6
6
]
T
a
i

e
t

a
l
.

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C
I

(
7
)
G
A
B
P
r
o
s
p
e
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t
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v
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n
d
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m
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p
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c
r
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s
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r
.

N
o
n
s
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g
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i
f
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t

t
r
e
n
d

t
o

(
p
a
r
t
i
a
l
)

b
e
n
e
f
i
t
[
6
7
]
R
o
w
b
o
t
h
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m

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t

a
l
.

S
C
I

(
5
)
L
e
v
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a
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R
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e
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n

p
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t
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:

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l
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n

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P

o
f

b
r
a
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n

o
r
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g
i
n
[
6
8
]
M
o
r
l
e
y

e
t

a
l
.

T
r
a
n
s
v
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(
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E
T
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(
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P

p
a
t
i
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n
t
s
)
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M
E
T

n
o
t

t
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d
[
6
9
]
W
a
d
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t

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C
I

(
4
)
P
l
a
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o
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a
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s
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o
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[
7
0
]
L
e
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d
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l
u

e
t

a
l
.

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(
2
0
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A
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e
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[
7
1
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(
2
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D
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n


o
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p
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[
7
2
]
S
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a
l

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a
l
.
S
C
I

(
1
3
7
)
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r
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M
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r
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n

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p
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[
7
3
]
A
M
Y
:

A
m
i
t
r
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p
t
y
l
i
n
e
;

C
B
D
:

C
a
n
n
a
b
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l
;

C
B
Z
:

C
a
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;

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C
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p
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C
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f
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n
t
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v
a
l
;

C
I
T
:

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i
t
a
l
o
p
r
a
m
;

C
M
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:

C
a
n
n
a
b
i
s
-
m
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d
i
c
i
n
a
l

e
x
t
r
a
c
t
s
;

C
P
:

C
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n
t
r
a
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p
a
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n
;

C
P
S
P
:

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t
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p
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D
E
X
:

D
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x
t
r
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m
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D
R
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D
r
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a
b
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l
;

G
A
B
:

G
a
b
a
p
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;

K
E
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:

K
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t
a
m
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L
A
M
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L
a
m
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t
r
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g
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;

M
E
T
:

M
e
t
h
a
d
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;

M
E
X
:

M
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x
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l
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t
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;

M
S
:

M
u
l
t
i
p
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s
c
l
e
r
o
s
i
s
;

N
N
T
:

N
u
m
b
e
r
-
n
e
e
d
e
d

t
o

t
r
e
a
t
;

N
P
:

N
e
u
r
o
p
a
t
h
i
c

p
a
i
n
;

S
C
I
:

S
p
i
n
a
l

c
o
r
d

i
n
j
u
r
y
;

S
R
:

S
u
s
t
a
i
n
e
d

r
e
l
e
a
s
e
;

T
H
C
:

T
e
t
r
a
h
y
d
r
o
c
a
n
n
a
b
i
n
o
l
;

V
A
L
:

V
a
l
p
r
o
a
t
e
.
Ca na ve ro & Bonic a lzi
1490 Expert Rev. Neurotherapeutics7(11), (2007)
C
P

o
f

b
r
a
i
n

o
r
i
g
i
n
L
e
i
j
o
n

a
n
d

B
o
i
v
i
e
C
P
S
P

(
1
5
)
C
B
Z
A
M
Y
R
a
n
d
o
m
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z
e
d
,

d
o
u
b
l
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b
l
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n
d
,

c
r
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s
s
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v
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r
,

p
l
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t
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l
l
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d
.

S
t
a
t
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s
t
i
c
a
l
l
y

s
i
g
n
i
f
i
c
a
n
t

p
a
i
n

r
e
l
i
e
f

f
r
o
m

A
M
Y

(
f
r
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m

C
B
Z

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n
l
y

f
r
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m

3
r
d

w
e
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k
)
.

N
N
T

C
B
Z
:

3
.
4

(
9
5
%

C
I
:

1
.
7

1
0
5
)
,

N
N
T

A
M
Y
:

1
.
7

(
9
5
%

C
I
:

1
.
1

3
.
0
)

[
7
4
]
M
c
Q
u
a
y

e
t

a
l
.
C
P
S
P

(
9
)
D
E
X
R
a
n
d
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m
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z
e
d
,

d
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l
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l
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n
d
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p
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s
s
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v
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r
.

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n
t
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r
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l

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-
o
f
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1

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e
s
i
g
n
.

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E
X

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n
e
f
f
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c
t
i
v
e
[
7
5
]
V
e
s
t
e
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g
a
a
r
d

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t

a
l
.
C
P
S
P

(
9
/
4
)
C
I
T
/
P
l
a
c
e
b
o
R
a
n
d
o
m
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d
,

d
o
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b
l
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n
d
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p
a
r
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l
l
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l
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p
l
a
c
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b
o
-
c
o
n
t
r
o
l
l
e
d
;

C
I
T

i
n
e
f
f
e
c
t
i
v
e
[
7
6
]
V
e
s
t
e
r
g
a
a
r
d

e
t

a
l
.
C
P
S
P

(
3
0
)
L
A
M
R
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n
d
o
m
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z
e
d
,

d
o
u
b
l
e
-
b
l
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n
d
,

p
l
a
c
e
b
o
-
c
o
n
t
r
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l
l
e
d
,

c
r
o
s
s
o
v
e
r
.

N
o

s
i
g
n
i
f
i
c
a
n
t

e
f
f
e
c
t
s

a
t

l
o
w
e
r

d
o
s
e
s
.

P
a
i
n

s
c
o
r
e

r
e
d
u
c
t
i
o
n
:

a
p
p
r
o
x
i
m
a
t
e
l
y

3
0
%

(
m
e
a
n
i
n
g
f
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l

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e
d
u
c
t
i
o
n

i
n

p
a
t
i
e
n
t
s

o
p
i
n
i
o
n
)
.

N
N
T

L
A
M
:

n
o
t

a
p
p
l
i
c
a
b
l
e
[
7
7
]
H
e
i
s
k
a
n
e
n

e
t

a
l
.

C
P
S
P

(
2
)
D
E
X
M
i
x
e
d

p
o
p
u
l
a
t
i
o
n

o
f

2
0

p
a
t
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e
n
t
s

w
i
t
h

N
P
.

R
e
s
u
l
t
s

n
o
t

s
p
l
i
t

d
o
w
n

a
c
c
o
r
d
i
n
g

t
o

p
a
i
n

t
y
p
e
[
7
8
]
L
a
m
p
l

e
t

a
l
.
P
r
e
v
e
n
t
i
o
n

o
f

C
P
S
P

(
3
9
)
A
M
Y

e
x
t
e
n
d
e
d
-
r
e
l
e
a
s
e
R
a
n
d
o
m
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z
e
d
,

d
o
u
b
l
e
-
b
l
i
n
d
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Ce ntra l pa in syndrome : e luc ida tion of ge ne sis a nd tre a tme nt
www.future-drugs.com 1491
T
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Ca na ve ro & Bonic a lzi
1492 Expert Rev. Neurotherapeutics7(11), (2007)
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Ce ntra l pa in syndrome : e luc ida tion of ge ne sis a nd tre a tme nt
www.future-drugs.com 1493
drugs that have a proven benefit for brain CP, while both
appear more or less ineffective for CP of cord origin. Although
not submitted to formal studies, mexiletine is a valuable drug,
especially in combination with gabapentin/pregabalin; gabap-
entin/pregabalin by themselves are effective in only some
patients [1]. Many other drugs, including opioids, have been
tried, with most patients not benefiting or only mildly so [47].
Cannabinoids do not seem to have advanced therapy to a
meaningful extent. It should also be recalled how all these
drugs have side effects that limit their use, above all in special
patient populations, for example in the elderly and spinal
injured patients (e.g., the anticholinergic effects of amitriptyl-
ine); some have rare, but major toxicities (e.g., StevensJohn-
son syndrome during lamotrigine assumption). Several of the
newer antiepileptics (e.g., topiramate) have not fulfilled the
promise, and neither have some recent antidepressants (e.g.,
reboxetine and selective serotonin reuptake inhibitors) [1].
Electrical neuromodulation
As far as brain CP is concerned, the technique of choice is
extradural cortical stimulation (ECS) of the primary motor or
sensory cortex contralateral to pain [48]. This is a minimally
invasive neurosurgical technique in which a stimulating paddle
is inserted through two burr holes or a small craniotomy on
the dura overlying the appropriate area that covers the painful
region [49]. More than half of patients derive a pain reduction
greater than 40% at 4 years [49]. No mortality or permanent
morbidity (including the kindling of an epileptic syndrome)
have been reported in hundreds of reported cases ever since its
introduction in 1989 [48]. Both spontaneous and evoked com-
ponents are favourably altered. Patients may be selected for
ECS on the basis of pharmacological dissection with GABA
agonists (propofol and barbiturates) [40,50] and trials of tran-
scranial magnetic stimulation, in which stimuli are applied
from an external source [51]. Deep brain stimulation (DBS), in
which one or two electrodes are inserted into the sensory thala-
mus or mesencephalon (periaqueductal/periventricular gray
areas), has dubious effects and may be burdened with rare
mortality and less rare permanent disabling morbidity (glo-
bally 1.4%) [1,52]. DBS has a long history, having being intro-
duced for the treatment of CP in the 1960s: experience over
the years has not borne out initial results [5355]. Spinal cord
stimulation (SCS), in which a paddle is applied to cord seg-
ments extradurally, plays no role for brain CP. For CP of cord
origin with at least partially preserved lemniscal sensibility,
SCS is the primary technique, but often loses effect within
1 year [1,52]. In failures or cases with complete loss of sensibil-
ity, in which SCS is totally ineffective, the choice rests between
ECS and DBS; unfortunately, not enough patients have
accrued to evaluate ECS, and DBS is often ineffective. Trans-
cutaneous electrical nerve stimulation, although the least inva-
sive of all electrical neuromodulatory procedures, is of scarce
benefit in the vast majority of patients and must be applied
several times a day, hindering activities of daily living. If
elected, it is best added on to oral drug therapy [1,52]. Some
patients have been submitted to electroconvulsive therapy with
mixed results; thisis a technique of last resort in highly refractory
cases[52,56].
Chemical neuromodulation
Several drugs have been infused into the subarachnoid space in
order to control CP. However, no evidence-based recommenda-
tion are possible; only anecdotal evidence exists and the few
controlled studies lack enough power and follow-up. A
GABAergic agent, such as baclofen or midazolam, can be
infused through a chronically implanted pump; this is most
effective in combination with clonidine, an adrenergic agent
[1,52]. Opioidsare only rarely effective and, in the long term, have
major endocrinologic and immunologic toxicity [1]. Ziconotide,
a recently approved drug, appearsto be insignificantly effective
on CP and unsafe [57].
Neuroablation
For many years, since the introduction of stereotactic surgery
at the end of the 1940s, neurosurgical ablative techniques,
such as thalamotomies and mesencephalotomies, have been
offered to distraught patients, but results have not held up over
time in most studies, in particular on spontaneous compo-
nents of CP [1,14]. Furthermore, mortality and permanent mor-
bidity often offset an initially positive result. Cingulotomy has
proven of no benefit on the sensory components of CP [1].
Surgery on the cord, including cordectomies and DREZ
coagulations, may relieve evoked and paroxysmal components
in some patients over the long term, but with unacceptable
morbidity [1,14]. The only ablative technique that makes sense
in light of the discussed pathophysiology is a small stereotactic
lesion deep in the corona radiata/internal capsule in order to
interrupt the descending arm of the corticothalamic loop; this
has been confirmed recently in a patient with post-stroke
central pain totally and immediately relieved by subparietal
leukotomy/capsulotomy [58].
Five - ye a r view
For 115 years, CP has been downplayed or downright ignored
by neurologists, being considered a mere curiosity. Studies over
the past 15 years have overturned the conviction of CP being
rare. Nonetheless, even today most neurologists and pain
therapists across the board, including some who contribute to
the scientific literature, have scarce appreciation of the clinical
features of CP, making misdiagnosis or underdiagnosis the norm
rather than not. Even when a correct diagnosis is made, patients
generally are treated according to tradition more than science.
Thistranslatesinto major suffering on the part of patients.
Recent advances, including the clarification of the genesis of
CP, have not yet reached the pain therapists in a rational way.
This is owing to two major reasons: the first is a lack of a pain
medicine specialty; and the second is an inability of those few
who made the advancements possible to interact sensibly in
divulging these advancements. International organizations,
such as the International Association for the Study of Pain
Ca na ve ro & Bonic a lzi
1494 Expert Rev. Neurotherapeutics7(11), (2007)
(IASP), have not affected the clinical practice in a tangible way.
However, when recent progress will reach a vaster professional
audience, the outlook for these patients will improve. In the
not too distant future, neural repair techniques, such as trans-
plantation of stem or engineered cells, might be able to achieve
neural restoration and pain relief without the dangers of con-
temporary techniques [59]; but what is clear is that we now
have a rational therapy (subparietal leucotomy/capsulotomy)
for patients not responding to drug therapy and electrical
stimulation. The challenge for pain therapists is to apply it.
Informa tion re sourc e s
PainOnline
www.painonline.com
Central Pain Syndrome Information Resource
www.painonline.org
Central Pain Syndrome Alliance (CPSA)
www.centralpain.org
Fina nc ia l & c ompe ting inte re sts disc losure
Theauthorshaveno relevant affiliationsor financial involvement
with any organization or entity with a financial interest in or
financial conflict with thesubject matter or materialsdiscussed in
the manuscript. This includes employment, consultancies, hono-
raria, stock ownership or options, expert testimony, grantsor patents
received or pending, or royalties.
No writing assistancewas utilized in the production of this
manuscript.
Key issues
Central pain (CP) affectsseveral millionsof patientsworldwide.
The main sourcesare brain strokes, spinal injuriesand multiple sclerosis.
The generator of CP isa deranged corticothalamic loop between the sensory cortex and the sensory thalamus.
Amitriptyline, lamotrigine and mexiletine are the first-line drugsfor CP, with a secondary role of gabapentin/pregabalin.
Extradural cortical stimulation isthe most effective neurosurgical technique available for CP.
Stereotactic subparietal leucotomy/capsulotomy isthe surgical technique best poised to relieve CP permanently in all patients.
In the future, neural restoration may achieve a cure without the complicationsof current therapy.
Re fe re nc e s
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Affilia tions
S Canavero, MD
Turin Advanced Neuromodulation Group
(Tang), CsoEinaudi 2, 10128 Torino, Italy
Tel.: +39 34 9471 7819
sercan@inwind.it
V Bonicalzi, MD
Turin Advanced Neuromodulation Group
(Tang), CsoEinaudi 2, 10128 Torino, Italy
vbonica@libero.it