treatment for central pain syndrome 2007
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Special Report
10.1586/14737175.7.11.1485 2007 Future Drugs Ltd ISSN 1473-7175 1485www.future-drugs.com
Central pain syndrome: elucidationof genesis and treatmentS Canaveroand V Bonicalzi
Author for correspondence
Turin Advanced Neuromodulati on
Group (Tang), Cso Einaudi 2,
10128 Tori no, I taly
Tel.: +39 34 9471 7819
sercan@inwind.it
KEYORDS:central pain, leukotomy,motor cortex stimulation,neuromodulation
Central pain (CP), namely, pain or allied symptoms that follow damage to the CNS, has
rem a ined a n obscure neurologica l syndrome with no e xplana tion or effec tive trea tment
since Edinge rs de sc ription in 1891. Onc e be lieve d to b e ra re , CP is now know n to affe c t
seve ra l millions of pe ople worldw ide, m a king it a t le a st as fre que nt as, for exa m ple,
Parkinsons disease. It follows such common entities as stroke, spinal cord injury and
multiple sclerosis, but also many other conditions, including neurosurgical procedures on
the brain a nd spine. A disturba nce of tha lam oc ortica l transm ission is now a ck nowled ge d
to be the ma in e ngine o f CP. When drugs fail, neuromod ulation, both elec trica l and
c hem ica l, provide relief to m a ny drug nonre spond e rs. A sma ll stereota c tic le sion dee p in
the subpa rie tal white ma tte r promise s c om plete relief, without the rava ge s of
neuroablation as performed widely in the past.
Expert Rev. Neurotherapeutics7(11), 14851497 (2007)
Historica l note
In 1888, Frau R, having agonized with terriblepains for 2 years, committed suicide; not evenopium could relieve her pains, which followedcerebral infarction. By studying this case, in1891, Dr Edinger, a doctor working in Frank-furt-am-Mein, Germany, published his seminalpaper in which he hypothesized the existenceof centrally arising pains [1,2]. The concept thatpain could be released independently ofperipheral nociceptive stimulation was born.
Actually, patients suffering central pain (CP)had already been described by other authors,both in western and eastern sources, at leastsince the early 1800s; nonetheless, nobodyactually intuited that brain damage alone could
trigger spontaneous, unrelenting pain [1]. In1938, Riddoch published his three-part reviewof CP in Lancet, establishing it as a definitenosological entity [3]. By that time, it was clearthat CP could follow brain damage at severallevels (cortex, subcortex, thalamus and brain-stem), but also spinal cord injury (SCI; so-called paraplegic pain), as amply noted duringWorld War I [1].
In 1906, Dejerine and Roussy described theso-called thalamic syndrome, in which, amongother symptoms and signs due to thalamic
stroke, was pain [4]. A few years later, the schol-arly paper by Head and Holmes clearly definedthe sensory deficits that characterize CP in anunparalleled description that has not beensurpassed to this day [5]. Unfortunately, focuson the thalamus sidelined the cortex and otherbrain areas and for the best part of the 20thcentury CP was considered to be mainly dueto thalamic stroke. Only with the advent ofCT scans (1973) and MRI (1981), it becameclear that pure thalamic lesions are not theprimary triggers [1].
Finally, during the 1990s, a series of epide-miological studies found CP to be a major,under-recognized entity, a fact underscored bya steep increase in the number of articles
appearing in the literature.
Definition & epidemiology
CP is, in fact, an all-encompassing term thatdefines pain, but also dysesthesias, paresthesiasand, as recently realized, pruritus [6], initiatedby a CNS lesion impinging on or interferingwith the spinothalamic tract en route to theparietal somatosensory areas, in other words,the path responsible for conduction of nocice-ptive and thermal stimuli [1]. The anatomicbasis of CP was highlighted in a major work
CONTENTS
Historica l note
Definition & ep idem iology
Clinical features &
diag nostic eva luation
Na tura l history
Ge nesis of ce ntra l pa in
Expert comm entary on
therapy
Five- yea r viewInformation resources
Financial & competing
intere sts d isc losure
Key issues
References
Affiliation s
For rep rint orde rs, p lea se co ntac t rep rints@future -d rugs.co m
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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 inthe CNS [1].
Several terms have been attached to CP. Besides thalamicpain, pseudothalamic pain has been used to define pain due to
suprathalamic lesions, while anesthesia dolorosa has also beenreferred to pain following neurosurgical-induced deafferenta-tion. Dysesthetic pain is another popular term. CP after spinalinjury has been referred to as, among many others, paraplegicpain or remote pain (as opposed to end-zone pain). All theseterms must be discarded in favor of the much more descriptiveterminology of CP of brain or brainstem origin (as seen inmedullary stroke, i.e., Wallenbergs syndrome) and CP of cordorigin [1].
Long considered to be a neurological rarity, based on sheeropinion and poor epidemiological observations, we now knowthat 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 numberof patients with other neurological conditions suffer CP, thusrunning in the millions worldwide [1]. In the USA alone, no lessthan 600,000 patients suffer CP [1], ten-times more than previ-ous estimates. Males are generally more represented, in olderage in the case of stroke, in younger age after SCI, with theexception of MS, which predominantly affects females. Anoften unrecognized cause of CP is iatrogenic lesions: CP maybe a complication of neurosurgical procedures both on thespine and the brain, ranging from disc ablation at dorsal levelsto 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 ofneurosurgical pain-relieving procedures (e.g., thalamotomies,mesencephalotomies and cordotomies) triggering new pain, inother words, CP, is a well recognized fact [7].
Approximately 1% of all epileptic patients suffer painful fitsat least once: we consider this a CP-allied condition, sincethere is no actual damage to the parietal projection of the spi-nothalamic tract. Nonetheless, the end cells of this pathway arelikely involved [1]. For a long time, dysesthetic pain as reportedby some patients with Parkinsons disease has been considereda form of CP, but recent studies do not confirm this view [13].
Clinical features & diagnostic evaluation
CP comes in three components [14]:
A constant, spontaneous pain (which may be described asaching, burning, pricking, lacerating or cramping), dysesthe-sias, paresthesias pruritus or combinations thereof. Typically,more than one kind of pain is experienced in 99% of thepatients and cord CP and MS-associated CP tend to be moredysesthetic [15];
A spontaneous, intermittent, generally lancinating, pain,which is experienced by approximately 1020% of the cases;
Evoked pain, experienced by approximately two-thirds of thepatients (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 beelicited by mechanical (static or dynamic) or thermal (coldmore than heat) stimuli. In cases described as hyperpathic, painis 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 entirehalf of the body and persists for an unusually long time afterstimulation has ceased. Evoked pain and intermittent shootingpains can hinder daily activities, as innocuous maneuvers cantrigger fits of intolerable pain. Patients may have to wear a glovewhen the hand is most affected. All these anomalous sensationsare referred inside a larger area of sensory loss or hypesthesia, on
the side of the body contralateral to the damage. Pain may befelt 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 sideof the face ipsilaterally and the rest of the hemisoma contralat-erally (Wallenbergs syndrome), following brainstem injury. CPafter SCI (both complete and incomplete) may involve theentire body region below the level of injury, but usually is moreintense in the sacral dermatomes, buttocks, genitalia and thefeet. Signs of dystrophy in the affected area may be observed insome CP patients [1,14].
The intensity of the pain varies from mild, unpleasanttingling to one of the most agonizing torments known tohumans. CP greatly impairs quality of life, interfering withsleep patterns and driving some to suicide. Its highly unpleasantquality disables patients even when intensity is low [1,14].
Diagnosis of CP is rather straightforward when a patientlaments 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 beassessed clinically with cold (e.g., an ice cube) and warm stim-uli, and pinprick. Frequently, evoked pain will be elicited. Inthe evaluation of the single patient, pain scales can beemployed, 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), allpatients 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; alesion (ischemic or hemorrhagic lesion, tumor or demyelinatingplaque) 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 isoften seen after CNS damage, and this must be differentiatedfrom CP [1].
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Na tura l history
CP generally starts days, weeks or months after the CNSinsult, but may present suddenly or take 1 or more years todevelop [1]; when the delay is in the 1-year range after SCI, asyrinx may be found on MRI [15]. Once set in, CP remainswith the patient for their lifetime in the vast majority of thecases. 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 tendsnot to change significantly, except in degree, over time, cord
CP may change remarkably over the years:it may increase in severity for several yearsand even change in distribution and qual-ity, sometimes dramatically in severalcases [1,15].
Careful studies reveal that CP may
completely and suddenly regress afterremoval of the inciting lesion in somepatients [1618]. Similarly, a further strokealong the parietothalamic axis may abol-ish the pain [1,19]. These observationshave pathophysiological consequences(see later).
Genesis of central pain
Scores of different theories have beenproposed to explain CP, both in the pastand recently (FIGURE 1)[1]. For a long time,
the thalamus has played a starring role inmost of them. Animal studies over thelast 20 years have not added to the field,for the simple reason that brain structureand neurochemistry differ significantly inthe human (for a discussion see [1]). Inthe end, a theory in biomedicine is goodif it leads to therapeutic advances. In thissense, most theories failed.
The highly popular view that both cen-tral and peripheral neuropathic pain canbe understood inside the framework of so-called deafferentation pain [14] has nevermade it into international classificationsand, although sharing similar paindescriptors, differences between them areso numerous to nullify a pathophysiologi-cal utility of such grouping. For instance,while brachial plexus avulsion painresponds well to standard dorsal rootentry zone (DREZ) lesions, CP of cordorigin does not; similarly, thalamic stimu-lation and thalamic surgical lesions are byfar more effective for peripheral neuro-pathic pain than CP [1]. Subhypnotic pro-
pofol can relieve CP, but only rarelyperipheral neuropathic pain [20].
In recent years, it has become clear that CP must be under-stood inside a framework that includes both the thalamus andthe sensory (SI and perhaps SII) cortex [19,21]. In particular, it isa derangement of the oscillatory pattern inside the sensory cor-ticothalamocortical loop that best explains the pathophysiologyof CP (dynamic reverberation theory of CP) [19].
In-depth recordings in the patients brains pointed to severalanomalies in the brainstem, thalamus and cortex [1,14]. Inparticular, hyperactivity in the form of bursting activity in thethalamus, 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 thalamic nuclei isthe large descending corticothalamic projection responsible for
maintaining central pain. Subparietal leucotomy/capsulotomy targetsthisprojection.
Vim
Vc
PulvinarTRN
CL
GABA interneurons
Spinothalamic tractSpinoreticular tractMedial lemniscus
Reticularformation
Neuromodulatory
brainsteminfluences
SI-MI
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considered a marker of a local dysrhythmia [21,22], but this hasbeen challenged, as bursting is a modality of transmission of thenormal brain [23]. Conversely, a disturbance in neural patternsof activity applies both to CP and also many other neurologicdisorders, 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 ofinciting lesions [25]or a further stroke [19]clearly suggests thatplasticity cannot underlie constant pain: both would be revers-ible in such circumstances [18]. Moreover, careful studies byTaskers group reveal major differences between what occurs inthe human patient and the experimental animal in terms ofplastic changes [26].
Importantly, CP has been cancelled by lesions interruptingthe thalamocortical loop in the subparietal corona radiata and
internal capsule [1,19]. Careful analysis of such cases revealsthat it is the much larger descending arm of the thalamocorti-cal loop that is key to maintaining CP over time [1,19]. A rolein feeding the loop comes from hyperactive reticular cellsspread along the spinotruncothalamic axis, whose destructionmay help allay CP [9,27]: this has been highlighted by studiesdealing with mesencephalic reticulotomy [28] and extendedDREZ-tomies [29]. The difference between subparietal lesionsand these latter lesions lies in the rate of disappearance of CP:sudden versus gradual.
Hyperexcitation of the spinothalamic pathway by thereticulothalamic system, which in turn is modulated by themedial 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]). Studiesinvestigating 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 prefrontalareas) [34]. A recent study adopted this view: the evidence ofblood flow, stimulation, and lesion studies forcefully make thecase that (thalamic primary sensory nucleus) ventral caudalnucleus 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 onethalamus or sensory cortex [19,33]. Clinical observations alsosupport the possibility for a unilateral CNS lesion to triggerbilateral CP [3739].
It has been proposed that a certain quota of people may begenetically predisposed to develop CP [1]. In fact, a lesion any-where along the spinothalamocortical pathway only triggers CPin 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 thatdifferential sparing of the lemniscal system as compared withthe spinothalamic system may trigger dysesthetic pain [15].Neuropharmacological data with GABA agonists in humanpatients 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 theoscillatory pattern along the thalamocortical loop responsiblefor conscious sensory processing, starting in the somatosensorycortex [1].
In this context, anomalies seen in the cingular and temporalareas are unspecific findings present in most chronic painpatients and not the basis of CP. According to Craig, CPwould be subtended by a hyperactive spinothalamocingularpathway after selective damage to a specific spinothalamo(ven-tral medial posterior nucleus [VMpo])insular pathway [41]. Itis worth recalling how this thermosensory disinhibitionhypothesis [41]not only has been completely disproven [1]on
clinical and neurophysiological grounds, but also its anatomicfoundations have been totally refuted. In the words of Jones:The construction does not stand up to cri tical examina-tion The VMpo is like one of those religious apparitionsthat appear to few but become believed by many (a) dogmathat rests upon the faith of conviction rather than upon docu-mented evidence evidence of never having spoken to apatient with chronic pain [42].
On the other hand, the different components of evoked painmost likely recognize different pathophysiological mechanisms,such as thermal versus mechanical allodynia [1,34,43]. Centralsensitization would play a major role in the genesis of thesepains [1,14,43].
The sympathetic nervous system plays no role whatsoever inthe genesis or sustenance of CP [1,4446].
Expe rt co mm entary on therap y
CP is best understood as a cancer of the spiri t, which nibblesaway each day at the patients quality of life, until severe disrup-tion in daily living inexorably sets in. Thus, it is of the utmostimportance that, unlike what happens for most patients, valua-ble time is not lost trying a smorgasbord of drugs, which areoften useless. If a trial of oral pharmacotherapy produces nobenefit within 6 months, neuromodulation must be the nextoption, without further delay.
Drug therapy
In recent years, the choice of drugs has become more evidencebased, owing to the effort of a handful of groups around theworld interested in CP. TABLE1lists oral drugs submitted to con-trolled studies. Unfortunately, all such studies suffer from tooshort a follow-up and low powering; on the other hand, theyare the best evidence upon which to base recommendations.Several effective agents have been identified, but many are notsuitable for oral intake. Parenteral drugs, while not useful forchronic therapy, nonetheless helped elucidate CP mechanisms(TABLE 2) [40]. Lamotrigine and amitriptyline are the only oral
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Table2.
Pharmacologicaltreatm
entofcentralpain:parenteraldrugs.
Author(s)
Paintype
Studyresults
Ref.
GABA
ergicagen
ts
Propofol
iv.
Canaveroe
ta
l.;
CanaveroandBonicalzi
CPSP,SCI
Painandallodyniaabolitioninpropofol-responsivepatients.Continu
ous(624h)iv.infusioninpropofol-respon
sive
patients:temporarilyeffectivewithpost-effectlastinghours
[83,84]
Sodi
umamylal
iv.
Mailise
ta
l.
SCI
VASreduction,dramatica
llodyniareductionandsubstantialhyperalg
esiareduction
[85]
Bac
lofe
nit
.
Hermane
ta
l.
CordCP
Significantdysestheticpainsuppression(thenspasm-relatedpain)
[86]
Margot-Duclote
ta
l.
SCI
>60%painreliefineightof14SCIpatients(betterresultsonparoxys
malpain)
[87]
Opioi
ds
Morph
ine
iv.
ArnerandMeyerson
CP
Ineffective
[88]
Portenoye
ta
l.
CP
Somebenefit
[89]
Kuperse
ta
l.
CPSP,SCI
Painsensoryratingnotaffected(trendtowardsincreasing);painaffe
ctratingsignificantlyreduced
[90]
Attale
ta
l.
CP
Nosignificantdifferenceinpainreductionbetweenmorphineandplacebo.Long-lastingtreatmentwithoralmo
rphine
effectiveonlyinthreeof14patientsat1218months
[91]
Kalmane
ta
l.
MS
Effectivein29%ofpatien
ts,onlyathighdoses
[92]
Fentanyl
iv.
DellemijnandVanneste
CP
Mixedpopulationof53NPpatients.Diazepamasactiveplacebo.Diazepam:noclinicallysignificanteffect.Beneficialeffect
offentanyl(independentofthetypeofNP)
[93]
Alf
enta
nili
v.
Eidee
ta
l.
SCI
Continuousandevokedpainmarkedlyreducedbyalfentanil(seealso
ketamineiv.)
[94]
Morph
ine
it.clon
idin
eit
.
Siddallet
al.
SCI
Painrelief:it.morphinealone=it.clonidine=placebo.it.morphine+it.clonidine:significantpainrelief.NNT
(combination):7.5
[95]
Opioi
dsan
tagonists
Naloxone
iv.
Baintone
ta
l.
CPSP
Ineffective
[96]
CP:Centralpain;CPSP:Post-strokecentralpain;it.:Intrathecal;iv.:Intravenous;MS:Multiplescle
rosis;NNT:Number-neededtotreat;NP:Neuropath
icpain;SCI:Spinalcordinjury;
VAS:Visualanaloguepainscale.
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Loca
lanest
heti
cs
Lido
cain
eiv
.
Attale
ta
l.
CPSP
SCI
Significanttemporarypain,brush-inducedallodyniaandstaticmechanicalhyperalgesiareduction.Long-lasting
painrelief
intwopatients.Sideeffec
tsintwoofthreepatients.NNT:5(SCIpatients)
[97]
Kvarrnstrome
ta
l.
SCI
Ketaminevslidocaine.No
significantanalgesiceffectfromlidocaine.
Frequentsideeffects
[98]
Finnerupe
ta
l.
SCI
Significantreductionofneuropathicat-levelandbelow-levelspontan
eouspain.Medianpainreduction:approxim
ately35%.
NNT(50%painrelief):3
[99]
Lido
cain
eit
.
LoubserandDonovan
SCI
Overalleffect:65%painrelief(mean)in12of16patients.Correlatingwithspinalcanalobstructionandsensory
blocklevel
[100]
NMDA
anta
gonists
Keta
min
eiv
.
Backonjae
ta
l.
CP
Painrelieflasting23h
[101]
Eidee
ta
l.
SCI
Continuousandevokedpainmarkedlyreducedbyketamine(seealso
alfentanil)
[94]
Kvarrnstrome
ta
l.
SCI
Ketaminevslidocaine.Sig
nificantanalgesiceffectfromketamineonly.Frequentsideeffects,especiallywithketa
mine.
Seealsolidocaineiv.
[98]
Oth
ers
4-am
inopyr
idin
eiv
.
Hanseboute
ta
l.
SCI
PainreductioninfiveofsixpatientswithincompleteSCI,noeffectin
twopatientswithcompleteandonesevere
incompleteSCI
[102]
Whole
-pla
ntc
anna
bis-
base
dmedic
ine
(-9-tetra
hydr
ocanna
bino
l:canna
bidi
ol)s
pray
Roge
ta
l.
MS
Meanchangeinpainintensity(atweek4):CBM:-2.7,placebo:-1.4(p=0.005).Cognitivesideeffects:impaired
long-term
memorystorage
[103]
S+k
etam
ine
iontop
horesis
Vrankene
ta
l.
CP
Nosignificantdifferences
inpainscores(VAS)betweenketamine(50
or75mg/day)andplacebo
[104]
Table2.
Pharmacologicaltreatm
entofcentralpain:parenteraldrugs(cont.).
Author(s)
Paintype
Studyresults
Ref.
CP:Centralpain;CPSP:Post-strokecentralpain;it.:Intrathecal;iv.:Intravenous;MS:Multiplescle
rosis;NNT:Number-neededtotreat;NP:Neuropath
icpain;SCI:Spinalcordinjury;
VAS:Visualanaloguepainscale.
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drugs that have a proven benefit for brain CP, while bothappear more or less ineffective for CP of cord origin. Althoughnot submitted to formal studies, mexiletine is a valuable drug,especially in combination with gabapentin/pregabalin; gabap-entin/pregabalin by themselves are effective in only somepatients [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 ameaningful extent. It should also be recalled how all thesedrugs have side effects that limit their use, above all in specialpatient populations, for example in the elderly and spinalinjured 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 thenewer antiepileptics (e.g., topiramate) have not fulfilled thepromise, and neither have some recent antidepressants (e.g.,reboxetine and selective serotonin reuptake inhibitors) [1].
Electrical neuromodulationAs far as brain CP is concerned, the technique of choice isextradural cortical stimulation (ECS) of the primary motor orsensory cortex contralateral to pain [48]. This is a minimallyinvasive neurosurgical technique in which a stimulating paddleis inserted through two burr holes or a small craniotomy onthe dura overlying the appropriate area that covers the painfulregion [49]. More than half of patients derive a pain reductiongreater than 40% at 4 years [49]. No mortality or permanentmorbidity (including the kindling of an epileptic syndrome)have been reported in hundreds of reported cases ever since itsintroduction in 1989 [48]. Both spontaneous and evoked com-ponents are favourably altered. Patients may be selected forECS on the basis of pharmacological dissection with GABAagonists (propofol and barbiturates) [40,50]and trials of tran-scranial magnetic stimulation, in which stimuli are appliedfrom an external source [51]. Deep brain stimulation (DBS), inwhich one or two electrodes are inserted into the sensory thala-mus or mesencephalon (periaqueductal/periventricular grayareas), has dubious effects and may be burdened with raremortality 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 overthe years has not borne out initial results [5355]. Spinal cordstimulation (SCS), in which a paddle is applied to cord seg-
ments extradurally, plays no role for brain CP. For CP of cordorigin with at least partially preserved lemniscal sensibility,SCS is the primary technique, but often loses effect within1 year [1,52]. In failures or cases with complete loss of sensibil-ity, in which SCS is totally ineffective, the choice rests betweenECS and DBS; unfortunately, not enough patients haveaccrued 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 scarcebenefit in the vast majority of patients and must be appliedseveral times a day, hindering activities of daily living. Ifelected, it is best added on to oral drug therapy [1,52]. Some
patients have been submitted to electroconvulsive therapy withmixed results; this is a technique of last resort in highly refractorycases[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 fewcontrolled studies lack enough power and follow-up. AGABAergic agent, such as baclofen or midazolam, can beinfused through a chronically implanted pump; this is mosteffective in combination with clonidine, an adrenergic agent[1,52]. Opioids are only rarely effective and, in the long term, havemajor endocrinologic and immunologic toxicity [1]. Ziconotide,a recently approved drug, appears to be insignificantly effectiveon CP and unsafe [57].
Neuroablation
For many years, since the introduction of stereotactic surgeryat the end of the 1940s, neurosurgical ablative techniques,such as thalamotomies and mesencephalotomies, have beenoffered to distraught patients, but results have not held up overtime 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 hasproven of no benefit on the sensory components of CP [1].Surgery on the cord, including cordectomies and DREZcoagulations, may relieve evoked and paroxysmal componentsin some patients over the long term, but with unacceptablemorbidity [1,14]. The only ablative technique that makes sensein light of the discussed pathophysiology is a small stereotacticlesion deep in the corona radiata/internal capsule in order tointerrupt the descending arm of the corticothalamic loop; thishas been confirmed recently in a patient with post-strokecentral pain totally and immediately relieved by subparietalleukotomy/capsulotomy [58].
Five- yea r view
For 115 years, CP has been downplayed or downright ignoredby neurologists, being considered a mere curiosity. Studies overthe past 15 years have overturned the conviction of CP beingrare. Nonetheless, even today most neurologists and paintherapists across the board, including some who contribute to
the scientific literature, have scarce appreciation of the clinicalfeatures of CP, making misdiagnosis or underdiagnosis the normrather than not. Even when a correct diagnosis is made, patientsgenerally are treated according to tradition more than science.This translates into major suffering on the part of patients.
Recent advances, including the clarification of the genesis ofCP, 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 painmedicine specialty; and the second is an inability of those fewwho made the advancements possible to interact sensibly indivulging these advancements. International organizations,such as the International Association for the Study of Pain
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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 professionalaudience, the outlook for these patients will improve. In thenot too distant future, neural repair techniques, such as trans-plantation of stem or engineered cells, might be able to achieveneural restoration and pain relief without the dangers of con-
temporary techniques [59]; but what is clear is that we nowhave a rational therapy (subparietal leucotomy/capsulotomy)for patients not responding to drug therapy and electricalstimulation. The challenge for pain therapists is to apply it.
Informa tion resourc es
PainOnlinewww.painonline.com
Central Pain Syndrome Information Resourcewww.painonline.org
Central Pain Syndrome Alliance (CPSA)www.centralpain.org
Financial & competing interests disclosure
The authors have no relevant affi liations or fi nancial involvement
wi th any organization or enti ty with a fi nancial interest i n or
fi nancial confli ct wi th the subject matter or materials discussed in
the manuscript. This includes employment, consultancies, hono-
raria, stock ownership or opti ons, expert testimony, grants or patents
received or pendi ng, or royalties.
No wri ti ng assistance was uti lized in the producti on of this
manuscript.
Key issues
Central pain (CP) affects several millions of patients worldwide.
The main sources are brain strokes, spinal injuries and multiple sclerosis.
The generator of CP is a deranged corticothalamic loop between the sensory cortex and the sensory thalamus.
Amitriptyline, lamotrigine and mexiletine are the fi rst-line drugs for CP, with a secondary role of gabapentin/pregabalin.
Extradural cortical stimulation is the most effective neurosurgical technique available for CP.
Stereotactic subparietal leucotomy/capsulotomy is the surgical technique best poised to relieve CP permanently in all patients.
In the future, neural restoration may achieve a cure without the complications of current therapy.
References
Papers of special note have been highlighted as:
of interest of considerable interest
1 Canavero S, Bonicalzi V.Central Pain
Syndrome. Pathophysiology, D iagnosis and
Management.Cambridge University Press,
NY, USA (2007).
This is the ultimate source on the subject.
The definitive cure for central pain is
presented and supported.
2 Edinger L. Giebt es central entstehende
Schmerzen?Dtsch Z. Nervenheil k1,
262282 (1891).
The paper which introduced the concept
of central pain.
3 Riddoch G. The clinical features of central
pain. Lumleian lecture. Lancet234,
10931098, 11501156, 12051209
(1938).
4 Dejerine J, Roussy G. Le syndrome
thalamique.Rev. Neurol.14, 521532
(1906).
5 Head H, Holmes G. Researches
into sensory disturbances from
cerebral lesions.Brain34, 102254
(1911).
Unsurpassed description of central
pain features.
6 Canavero S, Bonicalzi V, M assa-Micon B.
Central neurogenic pruritus: a literature
review. Acta Neurol. Belg.97, 244247
(1997).
7 Cassinari V, Pagni CA. Central Pain:
A Neurosurgical Survey.Harvard University
Press, USA (1969).
The book in which the anatomical basis of
central pain was defined.
8 Andersen G, Vestergaard K,
Ingeman-Nielsen M , Jensen TS. Incidence
of central post-stroke pain. Pain61,
187193 (1995).
9 Bowsher D. Stroke and central post-stroke
pain in an elderly population. J. Pain2,
258261 (2001).
10 Siddall PJ, Taylor DA, McClelland JM,
Rutkowski SB, Cousins MJ. Pain report and
the relationship of pain to physical factors
in the first 6 months following spinal cord
injury. Pain81, 187197 (1999).
11 Solaro C, Brichetto G, Amato MP, and the
PaISM study group. The prevalence of pain
in multiple sclerosis. A multicenter cross-
sectional study.Neurology63, 919921
(2004).
12 Gonzales GR, Tuttle SL, Thaler H T,
Manfredi PL. Central pain in cancer
patients. J. Pain4, 351354 (2003).
13 Djaldetti R, Shifrin A, Rogowski Z,
Sprecher E, M elamed E, Yarnitsky D.
Quantitative measurement of pain
sensation in patients with Parkinson
disease.Neurology22(62), 21712175
(2004).
14 Tasker RR. In: Central Pain States (3rd
Edition).Loeser JD (Ed.). Bonicas
management of pain, Lippincott Williams
& Wilkins, PA, USA 433457 (2001).
15 Beric A. Spinal cord damage: injury. In:
Textbook of Pain (4th Edit ion).Wall PD,
Melzack P (Eds). Churchill-Livingstone,
Edinburgh, UK 915927 (1999).
16 Canavero S, Bonicalzi V. Reversible central
pain. Neurol. Sci.22, 271273 (2001).
17 Kim LJ, Klopfenstein JD, Zabramski JM,
Sonntag VKH, Spetzler RF. Analysis of
pain resolution after surgical resection of
intramedullary spinal cord cavernous
malformations. Neurosurgery58, 106111
(2006).
18 Schott GD. Delayed onset and resolution
of pain. Some observations and
implications. Brain124, 10671076
(2001).
19 Canavero S. D ynamic reverberation: a
unified mechanism of central and phantom
pain. Med. Hypoth.42, 203207 (1994).
-
8/13/2019 Treatment for Central Pain Syndrome 2007
11/13
Ce ntra l pain syndrome : elucida tion of ge nesis a nd trea tme nt
www.future-drugs.com 1495
Original description of the
corticothalamic reverberation loop at the
basis of central pain.
20 Canavero S, Bonicalzi V, Pagni CA et al.
Propofol analgesia in central pain:
preliminary clinical observations. J. Neurol.
242, 561567 (1995).
21 Sarnthein J, Stern J, Aufenberg C,
Rousson V, Jeanmonod D. Increased EEG
power and slowed dominant frequency in
patients with neurogenic pain. Brain129,
5564 (2006).
22 Lenz FA, Dougherty PM. Experimental
and clinical aspects. In: Pain Processing In
The Human Thalamus.Steriade M,
JonesEG, McCormick DA (Eds). Elsevier,
The Netherlands 617652 (1997).
23 Radhakrishnan V, Tsoukatos J, Davis KD ,
Tasker RR, Lozano AM, Dostrovsky JO.
A comparison of the burst activity of lateral
thalamic neurons in chronic pain andnon-pain patients. Pain80, 567575
(1999).
The paper that killed the role of bursting
in the genesis of central pain.
24 Farmer S. Neural rhythms in Parkinsons
disease.Brain125, 11751176
(2002).
25 Pagni CA Canavero S. Functional thalamic
depression in a case of reversible central
pain due to a spinal intramedullary cyst.
Case report. J. Neurosurg.83, 163165
(1995).
26 Kiss ZHT, Dostrovsky JO, Tasker RR.Plasticity in human somatosensory
thalamus as a result of deafferentation.
Stereotact. Funct. Neurosurg.62, 153163
(1994).
27 Finnerup NB, Johannesen IL,
Fuglsang-Frederiksen A, Bach FW,
Jensen TS. Sensory function in spinal cord
injury patients with and without central
pain. Brain126, 5770 (2003).
28 Amano K, Kawamura H, Tanikawa T,
Kawabatake H, Iseki H, Taira T.
Stereotactic mesencephalotomy for pain
relief. A plea for stereotactic surgery.
Stereotact. Funct. Neurosurg.59, 2532
(1992).
29 Falci S, Best L, Bayles R, Lammertse D,
Starnes C. Dorsal root entry zone
microcoagulation for spinal cord injury-
related central pain: operative
intramedullary electrophysiological
guidance and clinical outcome.
J. Neurosurg.97, 193200 (2002).
30 Kim JS. Medial medullary infarct
aggravates central poststroke pain caused by
previous lateral medullary infarct.
Eur. Neurol.58, 4143 (2007).
31 Canavero S, Pagni CA, Castellano G et al.
The role of cortex in central pain
syndromes: preliminary results of
a long-term technetium-99
hexamethylpropyleneamineoxime single
photon emission computed tomography
study.Neurosurgery32, 185191 (1993).
32 Hirato M, Horikoshi S, Kawashima Y,Satake K, Shibasaki T, Ohye C. The
possible role of the cerebral cortex adjacent
to the central sulcus for the genesis of
central (thalamic) pain-a metabolic study.
Acta Neurochir. Suppl. (Wi en)58, 141144
(1993).
33 Canavero S, Bonicalzi V, Castellano G.
Two in one: the genesis of central pain.
Pain64, 394395 (1996).
34 Ducreux D, Attal N, Parker F,
Bouhassira D. Mechanisms of central
neuropathic pain: a combined
psychophysical and fMRI study insyringomyelia.Brain129, 963976 (2006).
35 Kim JH, Greenspan JD, Coghill RC,
Ohara S, Lenz FA. Lesions limited to the
human thalamic principal somatosensory
nucleus (ventral caudal) are associated with
loss of cold sensations and central pain.
J. Neurosci.27, 49955005 (2007).
36 Parrent AG, Lozano AM, Dostrovsky JO,
Tasker RR. Central pain in the absence of
functional sensory thalamus. Stereotact.
Funct. Neurosurg.59, 914 (1992).
In this paper, the possibility that central
pain is elaborated ipsilaterally to pain is
confirmed in the human patient.
37 Canavero S. Bilateral central pain.
Acta Neurol. Belg.96, 135136 (1996).
38 Kim JS. Delayed-onset ipsilateral sensory
symptoms in patients with central
post-stroke pain. Eur. Neurol.40,
201206 (1998).
39 Kim JS. Aggravation of poststroke sensory
symptoms after a second stroke on the
opposite side. Eur. Neurol.42, 200204
(1999).
40 Canavero S, Bonicalzi V. Review article.
The neurochemistry of central pain:
evidence from clinical studies, hypothesis
and therapeutic implications. Pain74,
109114 (1998).
41 Craig AD. A new version of the thalamic
disinhibition hypothesis of central pain.
Pain Forum7, 114 (1998).
42 Jones EG.The Thalamus (2nd Edi ti on).
Cambridge University Press, NY, USA
(2007).
The ultimate source on thalamic
anatomy and physiology. Featuring,
among others, the debunking of
Craigs ill-conceived theory.
43 Greenspan JD, Ohara S, Sarlani E,
LenzFA. Allodynia in patients with
post-stroke central pain (CPSP) studied by
statistical quanti tative sensory testing
within individuals. Pain109, 357366
(2004).
44 Schott GD. Nosological entities?
Reflex sympathetic dystrophy. J. Neurol.
Neurosurg. Psychiatr.71, 291295 (2001).
45 Ochoa JL. Truths, errors, and lies around
reflex sympathetic dystrophy and
complex regional pain syndrome.
J. Neurol.246, 875879 (1999).
46 Bonicalzi V, Canavero S. Sympathetic pain
again?Lancet360, 14261427 (2000).
47 Canavero S, Bonicalzi V. Chronic
neuropathic pain. N. Engl. J. Med.348,
26882689 (2003).
48 Canavero S, Bonicalzi V. Therapeutic
extradural cortical stimulation for central
and neuropathic pain: a review. J. Pain18,
4855 (2002).
49 Canavero S, Bonicalzi V. Extradural cortical
stimulation for central pain. In: Operative
Neuromodulati on. Neural Networks Surgery.
Sakas DE, Simpson B (Eds). Springer
Verlag, Germany 2736 (2007).
Complete explanation of the most
effective neuromodulation technique
available for central pain.
50 Canavero S, Bonicalzi V. Intravenous
subhypnotic propofol in central pain.
A double-blind, placebo-controlled,
crossover study. Cli n. Neuropharmacol.27, 182186 (2004).
51 Canavero S, Bonicalzi V. Transcranial
magnetic stimulation for central pain.
Curr. Pain Headache Rep.9, 8789 (2005).
52 Canavero S, Bonicalzi V. Neuromodulation
for central pain. Expert Rev.
Neurotherapeutics3, 591607 (2003).
53 Nandi D , Aziz T,Carter H, Stein J.
Thalamic field potentials in chronic central
pain t reated by periventricular gray
stimulation a series of eight cases.
Pain101, 97107 (2003).
54 Hamani C, Schwalb JM, Rezai AR,Dostrovsky JO, Davis KD, Lozano AM.
Deep brain stimulation for chronic
neuropathic pain: long-term outcome
and the incidence of insertional effect.
Pain125, 188196 (2006).
55 Rasche D, Rinaldi PC, Young RF,
Tronnier VM. Deep brain stimulation for
the treatment of various chronic pain
syndromes.Neurosurg. Focus21(6), E8
(2006).
56 Canavero S, Bonicalzi V. Electroconvulsive
therapy and pain. Pain89, 301302
(2001).
-
8/13/2019 Treatment for Central Pain Syndrome 2007
12/13
Ca nave ro & Bonica lzi
1496 Expert Rev. Neurotherapeutics7(11), (2007)
57 Bonicalzi V, Canavero S. Intrathecal
ziconotide for chronic pain. JAMA292,
16811682 (2004).
58 Koszewski W, Jarosz J, Pernak-De Gast J.
Stereotactic posterior capsulolentiform
deafferentation as an effective treatment in
central post-stroke pain. A new surgical
method for intractable central pain control?Pain Clini c15, 115123 (2003).
The first case to be relieved of central
pain following subparietal
leucotomy/capsulotomy as predicted
by Canavero.
59 Kondziolka D, Wechsler L, Achim C.
Neural transplantation for stroke.
J. Cli n. Neurosci. 9, 225230 (2002).
60 Davidoff G, Guarracini M, Roth E, Sliwa J,
Yarkony G. Trazodone hydrochloride in the
treatment of dysesthetic pain in traumatic
myelopathy: a randomized, double-blind,
placebo-controlled study. Pain29(2),151161 (1987).
61 Drewes AM, Andreasen A, Poulsen LH.
Valproate for treatment of chronic central
pain after spinal cord injury. A double-
blind cross-over study. Paraplegia32(8),
565569 (1994).
62 Potter PJ, H ayes KC, Segal JL et al.
Randomized double-blind crossover trial
of fampridine-SR (sustained release
4-aminopyridine) in patients with
incomplete spinal cord injury.
J. Neurotrauma15(10), 837849
(1998).
63 Chiou-Tan FY, Tuel SM, Johnson JC,
Priebe MM, Hirsh DD, Strayer JR.
Effect of mexiletine on spinal cord injury
dysesthetic pain.Am. J. Phys. Med. Rehabil.
75(2), 8487 (1996).
64 Haines DR, Gaines SP. N of 1 randomised
controlled trials of oral ketamine in patients
with chronic pain. Pain83(2), 283287
(1999).
65 Finnerup NB, Sindrup SH, Bach FW,
Johannesen IL, Jensen TS. Lamotrigine in
spinal cord injury pain: a randomized
controlled trial. Pain96(3), 375383
(2002).
66 Cardenas DD, Warms CA, Turner JA,
Marshall H, Brooke MM , Loeser JD.
Efficacy of amitriptyline for relief of pain in
spinal cord injury: results of a randomized
controlled trial. Pain96(3), 365373
(2002).
67 Tai Q, Kirshblum S, Chen B, Millis S,
Johnston M, DeLisa JA. Gabapentin
in the treatment of neuropathic pain after
spinal cord injury: a prospective,
randomized, double-blind, crossover trial.
J. Spinal Cord Med.25(2), 100105
(2002).
68 Rowbotham MC, Twil ling L, Davies PS,
Reisner L, Taylor K, Mohr D. Oral opioid
therapy for chronic peripheral and central
neuropathic pain.N. Engl. J. Med.348(13),
12231232 (2003).
69 Morley JS, Bridson J, Nash TP, Miles JB,
White S, Makin M K. Low-dose methadone
has an analgesic effect in neuropathic pain:a double-blind randomized controlled
crossover trial. Palli at. Med.17(7),
576587 (2003).
70 Wade DT, Robson P, House H, Makela P,
Aram J. A preliminary controlled study to
determine whether whole-plant cannabis
extracts can improve intractable neurogenic
symptoms.Cli n. Rehabil .17(1), 2129
(2003).
71 Levendoglu F, Ogun CO, Ozerbil O,
Ogun TC, Ugurlu H. Gabapentin is a first
line drug for the treatment of neuropathic
pain in spinal cord injury.Spine29(7),743751 (2004).
72 Carlsson KC, Hoem NO, Moberg ER,
Mathisen LC. Analgesic effect of
dextromethorphan in neuropathic pain.
Acta Anaesthesiol. Scand.48(3), 328336
(2004).
73 Siddall PJ, Cousins MJ, Otte A, Griesing T,
Chambers R, Murphy TK. Pregabalin in
central neuropathic pain associated with
spinal cord injury: a placebo-controlled
trial. Neurology67(10), 17921800 (2006).
74 Leijon G, Boivie J. Central post-stroke pain
a controlled trial of amitriptyline andcarbamazepine.Pain36(1), 2736 (1989).
75 McQuay HJ, Carroll D, Jadad AR et al.
Dextromethorphan for the treatment of
neuropathic pain: a double-blind
randomised controlled crossover trial with
integral n-of-1 design.Pain59(1), 127133
(1994).
76 Vestergaard K, Andersen G, Jensen TS.
Treatment of central post-stroke pain with a
selective serotonin reuptake inhibitor.
Eur. J. Neurol.3(Suppl. 5), 169 (1996).
77 Vestergaard K, Andersen G, Gott rup H,
Kristensen BT, Jensen TS. Lamotrigine for
central poststroke pain: a randomized
controlled trial. Neurology56(2), 184190
(2001).
78 Heiskanen T, H artel B, Dahl ML,
Seppala T, Kalso E. Analgesic effects of
dextromethorphan and morphine in
patients with chronic pain. Pain96(3),
261267 (2002).
79 Lampl C, Yazdi K, Roper C. Amitriptyline
in the prophylaxis of central poststroke
pain. Preliminary results of 39 patients
in a placebo-controlled, long-term study.
Stroke33(12), 30303032 (2002).
80 Morley JS, Bridson J, Nash TP, M iles JB,
White S, Makin M K. Low-dose methadone
has an analgesic effect in neuropathic pain: a
double-blind randomized controlled crossover
trial. Palli at. Med.17(7), 576587 (2003).
81 Svendsen KB, Jensen TS, Bach FW. Does
the cannabinoid dronabinol reduce central
pain in mult iple sclerosis?Randomiseddouble blind placebo controlled crossover
trial. Br. Med. J.329(7460), 253 (2004).
82 Notcutt W, Price M, Miller R et al. Initial
experiences with medicinal extracts of
cannabis for chronic pain: results from 34
N of 1 studies. Anaesthesia59(5),
440452 (2004).
83 Canavero S, Bonicalzi V, Pagni CA et al.
Propofol analgesia in central pain:
preliminary clinical observations.
J. Neurol.242, 561567 (1995).
84 Canavero S, Bonicalzi V. I ntravenous
subhypnotic propofol in central pain.A double-blind, placebo-controlled,
crossover study.Clin. Neuropharmacol.
27, 182186 (2004).
85 Mailis A, Amani N, Umana M, Basur R,
Roe S. Effect of intravenous sodium amytal
on cutaneous sensory abnormalities,
spontaneous pain and algometric pain
pressure thresholds in neuropathic pain
patients: a placebo-controlled study. I I.
Pain70, 6981 (1997).
86 Herman RM, DLuzansky SC, Ippolito R.
Intrathecal baclofen suppresses central pain
in patients with spinal lesions. A pilotstudy.Clin. J. Pain8, 338345 (1992).
87 Margot-Duclot A, Thiebaut J-B, Simon A,
Baud P, Adrianasolo H, Russel B. Effects of
intrathecal baclofen in cauda equina and
low spinal cord injury pain. In: 10th World
Congress on Pain, Book of Abstracts.IASP
Press, WA, USA A221P217 (2002).
88 Arnr S, M eyerson BA. Lack of analgesic
effect of opioids on neuropathic and
idiopathic forms of pain. Pain33, 1123
(1988).
89 Portenoy RK, Foley KM , Inturrisi CE.
The nature of opioid responsiveness and its
implications for neuropathic pain: new
hypotheses derived from studies of opioid
infusions. Pain43, 273286 (1990).
90 Kupers RC, Konings H, Adriaensen H ,
Gybels JM. Morphine differentially affects
the sensory and affective pain ratings in
neurogenic and idiopathic forms of pain.
Pain47(1), 512 (1991).
91 Attal N, Guirimand F, Brasseur L, Gaude V,
Chauvin M, Bouhassira D. Effects of I V
morphine in central pain. A randomized
placebo-controlled study.Neurology58,
554563 (2002).
-
8/13/2019 Treatment for Central Pain Syndrome 2007
13/13
Ce ntra l pain syndrome : elucida tion of ge nesis a nd trea tme nt
www.future-drugs.com 1497
92 Kalman S, Osterberg A, Sorensen J,
Boivie J, Bertler A. Morphine
responsiveness in a group of well-defined
mult iple sclerosis patients: a study with
iv. morphine. Eur. J. Pain6, 6980
(2002).
93 Dellemijn PL, Vanneste JA. Randomised
double-blind active-placebo-controlledcrossover t rial of intravenous fentanyl in
neuropathic pain. Lancet349, 753758
(1997).
94 Eide PK, Stubhaug A, Stenehjem AE.
Central dysesthesia pain after traumatic
spinal cord injury is dependent on
N-methyl-D-aspartate receptor
activation. Neurosurgery37, 10801087
(1995).
95 Siddall PJ, Molloy AR, Walker S,
Mather LE, Rutkowski SB, Cousins MJ.
The efficacy of intrathecal morphine and
clonidine in the treatment of pain afterspinal cord injury. Anesth. Analg.
91, 14931498 (2000).
96 Bainton T, Fox M, Bowsher D, Wells C.
A double-blind trial of naloxone in central
post-stroke pain. Pain 48, 159162
(1992).
97 Attal N, Gaude V, Brasseur L et al.
Intravenous lidocaine in central pain.
A double-blind, placebo-controlled,
psychophysical study.Neurology54,
564574 (2000).
98 Kvarnstrom A, Karlsten R, Quiding H,
Gordh T. The analgesic effect of
intravenous ketamine and lidocaine on painafter spinal cord injury. Acta Anaesthesiol.
Scand.48, 498506 (2004).
99 Finnerup NB, Biering-Sorensen F,
Johannesen IL et al. Intravenous lidocaine
relieves spinal cord injury pain. A
randomized controlled trial. Anesthesiology
102, 10231030 (2005).
100 Loubser PG, Donovan WH. Diagnostic
spinal anaesthesia in chronic spinal
cord injury pain. Paraplegia29, 2536
(1991).
101 Backonja M, Arndt G, Gombar KA,
Check B, Zimmermann M. Response ofchronic neuropathic pain syndromes to
ketamine: a preliminary study. Pain56,
5157 (1994).
102 Hansebout RR, Blight AR, Fawcett S,
Reddy K. 4-aminopyridine in chronic
spinal cord injury: a controlled,
double-blind, cross-over study in
eight patients. J. Neurotrauma10, 118
(1993).
103 Rog DJ, Nurmikko TJ, Friede T,
Young CA. Randomized, controlled trial of
cannabis based medicine in central pain in
multiple sclerosis. Neurology65, 812819
(2005).
104 Vranken JH, Dijkgraaf M G, Kruis MR,
van Dasselaar NT, van der Vegt MH.
Iontophoretic administration of
S+-ketamine in patients with intractable
central pain: a placebo-controlled trial.
Pain118, 224231 (2005).
Affilia tions
S Canavero, MD
Turin Advanced Neuromodulati on Group
(Tang), Cso Einaudi 2, 10128 Torino, I taly
Tel.: +39 34 9471 7819
sercan@inwind.it V Bonicalzi, MD
Turin Advanced Neuromodulati on Group
(Tang), Cso Einaudi 2, 10128 Torino, I taly
vbonica@libero.it
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