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

    [email protected]

    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

    http://www.future-drugs.com/http://www.future-drugs.com/
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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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    (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.

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    Affilia tions

    S Canavero, MD

    Turin Advanced Neuromodulati on Group

    (Tang), Cso Einaudi 2, 10128 Torino, I taly

    Tel.: +39 34 9471 7819

    [email protected] V Bonicalzi, MD

    Turin Advanced Neuromodulati on Group

    (Tang), Cso Einaudi 2, 10128 Torino, I taly

    [email protected]

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