THERAPY IN PRACTICE

Pharmacological Management of Central Post-Stroke Pain:A Practical Guide

Jong S. Kim

� Springer International Publishing Switzerland 2014

Abstract Pain is one of the most troublesome sequelae of

stroke. Some of this post-stroke pain is caused by the brain

lesion itself; this is called central post-stroke pain (CPSP).

Although the prevalence of CPSP is low (1–8 %), persis-

tent, often treatment-resistant, painful sensations are a

major problem for stroke patients. The pathogenesis of

CPSP remains unknown, but suggested underlying causes

include hyperexcitation in the damaged sensory pathways,

damage to the central inhibitory pathways, or a combina-

tion of the two. For pharmacological treatment, amitrip-

tyline, an adrenergic antidepressant, is currently the first-

line drug for CPSP. However, its effect is frequently

incomplete and a high dose is commonly not tolerated in

stroke patients. Lamotrigine, an antiepileptic, was also

found to be effective in a controlled trial and can be used as

an alternative or additive therapy. GABAergic drugs with

potential calcium channel-blocking effects, such as gaba-

pentin or pregabalin, have recently emerged as a poten-

tially useful therapy. These drugs are effective in various

neuropathic pain syndromes, but their effect on CPSP

remains to be proven. Pregabalin may improve pain-related

anxiety and sleep disturbances. Fluvoxamine and mexile-

tine may be used adjunctively in some patients. Non-

pharmacological treatments such as motor cortex stimula-

tion or deep brain stimulation are used in some centers, but

are not proven to be effective. Further well designed

clinical trials as well as basic research should be performed

to improve our understanding of the pathophysiology of

CPSP and to develop better treatment strategies.

Key Points

Management of the central post-stroke pain (CPSP)

is challenging, and there still are no universally

accepted management guidelines.

The use of adrenergic antidepressants (e.g.,

amitriptyline), antiepileptics (e.g., lamotrigine), or

their combination are currently reasonable

therapeutic approaches.

With an ever-increasing aged population, CPSP will

become an even more important problem in the

future. Further research and trials are needed.

1 Introduction

One of the most troublesome sequelae of stroke is pain,

which occurs in between 19 and 74 % of stroke patients

[1–7], depending on the characteristics of the patients, the

time of assessment, and the definition of pain. The most

common location of post-stroke pain is the shoulder, found

in 11–40 % of patients [1–4]. This joint pain is associated

with immobilization, spasticity, and contraction of the

paralyzed muscles in patients with severe limb paresis [8].

In addition, bedsores, peripheral neuropathy, anxiety, and

depression are causally associated with post-stroke pain.

Another important cause of pain in stroke patients is

‘‘central pain,’’ which refers to pain due to central nervous

system lesions. Central pain after a contralateral stroke has

been described since the 19th century [9, 10], and is

especially common after thalamic strokes [11]. Although

J. S. Kim (&)

Department of Neurology, Asan Medical Center, University of

Ulsan, Songpa-Gu, 388-1 Pungnap-Dong, Seoul 138-736, Korea

e-mail: jongskim@amc.seoul.kr

CNS Drugs

DOI 10.1007/s40263-014-0194-y

this phenomenon has been described as ‘‘thalamic syn-

drome’’ or ‘‘thalamic pain,’’ it is now widely recognized

that strokes occurring anywhere in the sensory tract can

produce similar central pain [12–15]. For this reason, the

term central post-stroke pain (CPSP) is now generally used

[16, 17], although many patients describe the symptoms

using terms such as ‘‘burning,’’ ‘‘cold,’’ or ‘‘squeezing’’

rather than as pain. Patients may have fluctuating or

intermittent symptoms [18–20].

CPSP occurs in 1–8 % of stroke patients [21, 22].

However, the delayed occurrence of symptoms, the lack of

objective diagnostic criteria, and the fluctuations in

symptom severity make it difficult to assess the prevalence

[23]. Currently, it is assumed that more than 30,000

patients suffer from CPSP in the USA [24]. With an ever-

increasing older population, CPSP will become an even

more important problem in the future.

Management of the CPSP is challenging, and there are

still no universally accepted treatment guidelines. Although

there have been general reviews on CPSP or its manage-

ment [25–28], there is a need for a review of the recent

progress in the management of CPSP. The aim of this paper

was to provide a succinct, clinically oriented guide to the

pharmacological management of CPSP based on available

evidence. Non-pharmacological therapies are also briefly

discussed. The present review highlights practical and

clinically relevant considerations rather than those of the-

oretical interest.

2 Clinical Features and Location of Lesions

Responsible for Central Post-Stroke Pain (CPSP)

CPSP may start at stroke onset, but more often its onset is

delayed. In some cases, the delay may be up to several

years [15, 22, 29]. The symptoms almost always develop

within the area of initial sensory impairment [30], usually

where the deficits are severe [19]. The symptoms may be

restricted to the hand and foot, or less commonly to

proximal body parts such as the thigh or shoulder. Spino-

thalamic abnormalities, particularly temperature-sensory

ones, are frequently associated with CPSP [13, 15, 30],

although patients with medial lemniscal sensory deficits

[19, 31] or without objective sensory deficits are also

encountered [13]. Dysesthesia [12, 17] and allodynia are

common [29]. CPSP has been variably described by its

sufferers as triggering ‘‘burning,’’ ‘‘aching,’’ ‘‘squeezing,’’

‘‘pricking,’’ ‘‘cold,’’ and ‘‘lacerating’’ sensations [12, 21],

and such symptoms are frequently aggravated by a cold

environment, psychological stress, heat, fatigue, or body

movement [30].

CPSP can occur after strokes affecting any part of the

sensory tract, but certain brain structures are more closely

associated. The thalamus is the classic and probably most

commonly involved structure in patients with CPSP [29,

32]. One study showed that 25 % of patients with thalamic

infarction involving the ventral posterior lateral nucleus

had CPSP [33]. Lenticulocapsular strokes occasionally

produce predominant sensory dysfunction [34] and sub-

sequent CPSP [20, 29, 32], although significant hemipa-

resis and resultant shoulder pain are also important. In

some patients, CPSP and nociceptive shoulder pain co-

exist. Cortical strokes, particularly those involving insular

or opercular areas, can produce CPSP [14, 22, 32, 35]. In

the pons, a dorsally located stroke involving ascending

sensory fibers can produce significant sensory dysfunction

and CPSP [36]. Sensory deficit occurs in more than 90 %

of patients with lateral medullary infarction [37], and CPSP

commonly develops in this condition. In one report, CPSP

occurred in 25 % of lateral medullary infarction patients

[38]. In medial medullary infarction, sensory deficit is the

second most important symptom, followed by motor dys-

function [39]. CPSP is also common in this condition [20,

39]. As motor dysfunction is also common in this condi-

tion, nociceptive joint pain often co-exists [19].

3 Pathogenesis of CPSP

The pathogenesis of CPSP remains unknown, but previous

reports have suggested mechanisms that include hyperex-

citation in the damaged sensory pathways, damage to the

central inhibitory pathways, or a combination of the two

[16, 23, 40]. It is highly likely that various neurotrans-

mitters are involved in this process. The thalamus was

believed to be responsible for the generation of CPSP.

According to Casey [41], the thalamic interneuron and

brainstem reticular formation normally inhibit the activity

of the thalamic relay neuron, whereas the spinal cord

activates the thalamic interneuron and brainstem reticular

formation. Thus, a spinal cord lesion can excessively

activate the thalamic relay neuron through disinhibition of

the thalamic interneuron and brainstem reticular formation.

Thalamic lesions may directly damage the thalamic inter-

neuron or the thalamic reticular nucleus (which normally

inhibits the thalamic relay neuron), increasing the activity

of the thalamic relay neuron.

Pieces of evidence suggest that structures that are

involved in the generation of CPSP are located beyond the

thalamus and include various cortical structures such as the

anterior cingulate cortex [42–44]. In normal subjects,

increased regional cerebral blood flow has been seen in the

area of the anterior cingulate cortex in response to pain

stimulation [45–51] that correlated with the subjects’

feelings of ‘‘unpleasantness’’ [48, 50]. However, in a pos-

itron emission tomography study, Peyron et al. [52] found

J. S. Kim

increased blood flow in the contralateral thalamus and

parietal area but decreased blood flow in the anterior cin-

gulate cortex after application of cold or electrical stimuli

to the painful limbs of patients with lateral medullary

infarction. The authors therefore speculated that the com-

bination of increased secondary somatosensory cortex (SII)

activity and decreased (or a failure to increase) anterior

cingulate cortex activity in response to innocuous stimuli

might be the brain response pattern specifically associated

with allodynia.

These results suggest that activation of the insular cortex

may be related to the generation of CPSP. Indeed, per-

ception of unpleasantness in skin and muscle has been

associated with bilateral insular activation [53]. However,

it remains unknown what actually happens in the insular

cortex of CPSP patients. Using positron emission tomog-

raphy, Craig et al. [54] found that contralateral brain

activity correlated with graded cooling stimuli only in the

dorsal margin of the middle/posterior insula in humans.

This region corresponds to the thermoreceptive- and

nociceptive-specific lamina I spinothalamocortical path-

way in monkeys and can be considered an enteroceptive

area within the limbic sensory cortex. On the basis of these

observations, Craig proposed that CPSP results from cen-

tral lesions affecting the pathways mediating cold sensation

that unmask (or disinhibit) cold-induced activation of the

polymodal C-fiber nociceptive pathway, which is respon-

sible for the sensation of burning cold pain [55]. This so-

called ‘‘thermosensory disinhibition hypothesis’’ seems to

be consistent with the common occurrence of impaired

thermal sensation and frequent complaint of ‘‘burning’’

sensation in CPSP patients, as well as the anatomical

locations of lesions coinciding with the ascending lamina I

spinothalamocortical pathway to the dorsal posterior insula

[55].

However, although most patients with CPSP have

impairment of spinothalamic sensory function, patients

with lemniscal sensory disturbances also develop long-

standing painful sensory symptoms [19]. This observation

recalls an old theory that painful sensory symptoms may be

due to disinhibition from a lesion affecting the medial

lemniscal pathway [56]. The interrelatedness of the two

(spinothalamic and lemniscal) main sensory systems may

be mediated by the spinoreticulothalamic sensory pathway

[13], which could possibly play a role in the genesis of

painful symptoms. Tasker and colleagues [13, 57] previ-

ously provided evidence that the spinothalamic and adja-

cent spinoreticulothalamic tracts are interrelated, such that

deafferentation of the former renders the normally nonex-

citable reticulothalamic system responsive to stimulation,

thus provoking painful sensations. Therefore, development

of CPSP following a spinothalamic tract injury may

depend, at least in part, on the presence of a relatively

intact reticulothalamic system [58]. It may be speculated

that lemniscal tract injury disinhibits the spinothalamic

system via the reticulothalamic system, ultimately pro-

ducing hypersensitivity of the spinothalamic sensations.

4 Treatment of CPSP

It is difficult to completely abolish CPSP once it has

developed. Medication is generally helpful, but is fre-

quently unsatisfactory. Before CPSP treatment begins, the

following should be considered. First, a physician should

confirm that the patient’s symptoms are CPSP rather than

pain caused by joint contracture, spasticity, or peripheral

nerve diseases through careful examination and diagnostic

tests. This is important because the treatment strategy

should differ according to the cause of the pain. Second, it

is important to educate the patient regarding the nature of

CPSP. Patients should be informed that pain relief might

not occur until a maximal dose of drugs is gradually

achieved over a certain period of time. They should also be

informed that treatment may be only partly effective and

that the goal of treatment is to reduce the pain burden

rather than to completely abolish the symptoms. Third,

patients with CPSP frequently have concomitant depres-

sion, anxiety, or sleep disturbances. Medication or behav-

ioral therapy aimed at improving these problems may have

to be contemporaneously initiated to maximize the thera-

peutic effect.

4.1 Pharmacological Treatment

As discussed above, CPSP may be related to the excitation

of neurons mediated through various chemicals in our

brain, including adrenergic, serotonin, and glutaminergic

neurotransmitters. Many drugs capable of modulating these

neurochemicals have been developed, and some of them

are used in clinical trials for the treatment of CPSP

(Table 1).

4.1.1 Antidepressants

In 1989, Leijon and Boivie [59] examined the efficacy of

amitriptyline in a double-blind, placebo-controlled, cross-

over study in patients with CPSP. They included patients

who sought remedy for constant or intermittent pain that

started after the stroke. Nociceptive pain and peripheral

neuropathic or psychogenic origin pain were excluded. In

this trial, amitriptyline 25 mg/day was gradually increased

up to 75 mg/day over 4 weeks. The daily pain score

(during the last week) and global rating of pain relief (on

the last day) were assessed. Among 15 patients tested,

improvement in pain was reported in one in the placebo

Management of Central Post-Stroke Pain

group and ten in the amitriptyline group, and the difference

was statistically significant. Although it enrolled only 15

patients, this was the first study to prove the efficacy of

amitriptyline in the treatment of CPSP.

A more recent, controlled, crossover study showed that

amitriptyline was significantly more effective than placebo

and that there was a nonsignificant trend suggesting that

amitriptyline may be more effective than gabapentin

(p = 0.061) in patients with central pain associated with

spinal cord injury [60]. Furthermore, amitriptyline is a

cheap and easily available drug. Therefore, amitriptyline

has been considered the first-line drug in the management

of CPSP. However, it is often only partially effective in

patients with severe symptoms or effective only when a

large dose (up to 100 mg/day) is administered. Unfortu-

nately, the side effects, such as dry mouth, urinary reten-

tion, somnolence, and confusion, are frequently intolerable

in aged stroke patients.

Another study investigated the effectiveness of ami-

triptyline for the prevention of CPSP in 39 patients with

thalamic stroke [61]. The results showed that CPSP

occurred in 21 and 17 % of patients receiving placebo and

amitriptyline, respectively, suggesting potential efficacy.

However, this difference was not statistically significant,

and there is no rationale for using this drug for the pre-

vention of CPSP.

Although their efficacies have not been properly inves-

tigated in patients with CPSP, similar antidepressants with

adrenergic activities, such as nortriptyline, desipramine,

imipramine, doxepin, and venlafaxine, are occasionally

used for patients in whom amitriptyline is not tolerated

[25]. Generally, serotonin uptake inhibitors are less effec-

tive for CPSP than adrenergic drugs. For instance, citalo-

pram was found to be ineffective in patients with CPSP

[62]. However, an open-label study showed that fluvox-

amine up to 125 mg/day was found to be moderately

Table 1 Important studies testing the efficacy of various drugs for CPSP

References Drug Study design Patient

no./

duration

of

treatment

Notable

inclusion

criteria

Daily dose Outcome

assessment

Results on

primary

outcome

Comments

Leijon and

Boivie [59]

Amitriptyline Double-

blind,

placebo-

controlled,

3-phase

crossover

15/4

weeks

Patients

should seek

remedy for

pain

Start with

25 mg,

up to

75 mg

Daily pain

rating

scale

(during the

last week).

Global

rating (on

the last

day)

Significant Effect independent of

changes in

depression.

Carbamazepine was

also tested

Vestergaard

et al. [69]

Lamotrigine Double-

blind,

placebo-

controlled,

crossover

30/8

weeks

Pain

intensity C4

Start with

25 mg,

up to

200 mg

Median pain

score

(during the

last week)

Significant Concomitant CPSP

medication not

allowed

Shimodozono

et al. [63]

Fluvoxamine Open-label 31/2–4

weeks

Start with

50 mg,

up to

125 mg

VAS pain

score

Significant Significant only when

stroke

occurred \1 year.

Depression not

correlated with pain

score. Patients

receiving CPSP drugs

excluded

Kim et al. [81] Pregabalin Double-

blind,

placebo-

controlled,

parallel

219/13

weeks

Average daily

pain score

C4 during

the last

week

Start with

150 mg,

up to

600 mg

Daily pain

ratingscale

(during the

last week)

Not

significant

Concomitant CPSP

medication allowed.

Improved secondary

outcome: sleep,

anxiety and

clinicians’ global

impression of

change. Primary

result significant up

to 8 weeks

CPSP central post-stroke pain, VAS visual analog scale

J. S. Kim

effective in patients with CPSP [63]; the average pain score

was reduced from 7.7 to 6.0 on a visual analog scale

(p \ 0.01). The effect was considered to be unrelated to the

anti-depressive effect of the drug.

4.1.2 Antiepileptic and Glutamatergic Drugs

Various antiepileptics have been tried in patients with

CPSP under the assumption that CPSP is related to neu-

ronal hyperexcitability in the sensory system. The efficacy

of carbamazepine was concomitantly examined in the trial

described above that investigated the efficacy of amitrip-

tyline [59]. In this double-blind, controlled study, car-

bamazepine up to 800 mg/day was not found to be superior

to placebo. However, there was a tendency for improve-

ment: five of 14 patients reported some pain relief, whereas

only one patient receiving placebo showed improvement.

The average pain score (4.2) after 4 weeks of treatment

was identical to that after amitriptyline treatment. How-

ever, the effect did not reach statistical significance when

compared with placebo, and no correlation was found

between the effect and plasma concentration. Therefore,

the efficacy of carbamazepine on CPSP was not proven.

Nevertheless, some physicians use carbamazepine as an

adjunctive therapy when the efficacy of antidepressants is

insufficient. Phenytoin has been shown to be efficacious in

some case series [64–66], but no double-blind trial has

been reported to date.

On the other hand, lamotrigine, a novel antiepileptic

drug that presynaptically inhibits sodium channels and

suppresses glutamate release, was reported to be moder-

ately effective for CPSP in both case series [67, 68] and in

a double-blind, placebo-controlled, crossover study [69]. In

the latter study investigating 30 patients, after 8 weeks of

treatment, the average pain score in the last week dropped

to 5 in the lamotrigine group (started with 50 mg/day and

titrated up to 200 mg/day), whereas the pain score

remained unchanged at 7 during placebo treatment. The

difference was statistically significant (p = 0.01).

Although three patients (all in the lamotrigine group)

withdrew from the study because of adverse effects (rash,

severe headache and severe pain, respectively), the drug

was generally well tolerated. The number of patients

reporting adverse effects was nearly identical: 17 in the

lamotrigine group and 18 in the placebo group. The benefit

was modest, and it was suspected by authors that a higher

dosage (400 mg/day) could have been more effective [69].

However, another placebo-controlled, crossover study

using lamotrigine up to 400 mg/day failed to show any

benefit in patients with central pain due to multiple scle-

rosis [70].

There has been postulation that CPSP is caused by

unbalanced glutamate/GABA neurotransmission in the

central nervous system, with relative hypofunction of the

GABAergic inhibitory system [71]. Therefore, GABAergic

drugs have been considered a potentially useful option for

the treatment of CPSP. Valproic acid and clonazepam have

been used in this context, but their efficacy has not been

solidly proven by controlled studies. These antiepileptics

may be effective at least in relieving paroxysmal, shooting

pains [72]. Zonisamide was reported to be effective in two

patients with CPSP due to thalamic stroke [73], whereas

topiramate, another GABAergic antiepileptic, was found to

be ineffective in diminishing central pain [74].

Recently, gabapentin, a structural analog of GABA, has

received special attention because it acts on pre-synaptic

voltage-sensitive calcium channels, which modulate the

release of multiple neurochemicals. Gabapentin was found

to be effective in relieving neuropathic pain due to

peripheral nerve disease [75] as well as central pain caused

by spinal cord lesions [76]. In a large, double-blind trial

involving neuropathic pain syndrome patients [77], the

authors enrolled 307 patients (gabapentin 153, placebo

152). Gabapentin was given in three divided doses, initially

titrated to 900 mg/day, followed by two further increases,

to a maximum of 2,400 mg/day if required. The primary

outcome was the change in the average daily pain score

(baseline vs. final week). Over the 8-week study, the score

decreased by 1.5 (21 %) in the gabapentin group and by 1.0

(14 %) in the placebo group. The difference was significant

(p = 0.048). Clinician and patient global impression of

change and some domains of quality of life (bodily pain,

social functioning and role-emotional) assessed using the

Short Form-36 (SF-36) Health Survey were significantly

better in the gabapentin group than in the placebo group.

Although gabapentin more often produced dizziness and

somnolence than placebo (38.6 vs. 13.2 %), the adverse

effects were generally tolerable and the percentage of

withdrawal due to adverse effects was identical (16 %) in

the two treatment groups. Unfortunately, among the

enrolled patients, only 3 % had CPSP, and studies exclu-

sively enrolling patients with CPSP are still unavailable.

Nevertheless, on the basis of these data, gabapentin is now

increasingly prescribed in patients with CPSP.

A closely related drug, pregabalin, was also found to be

effective in the treatment of various neuropathic pains,

including central pain due to spinal cord lesion [78–80].

Recently, a 13-week, randomized, double-blind, multicen-

ter, placebo-controlled study of 150–600 mg/day pregab-

alin was conducted in patients with CPSP [81]. The

primary efficacy endpoint was the mean pain score on the

Daily Pain Rating Scale over the last 7 days. Secondary

endpoints included patient-reported sleep and health-rela-

ted quality-of-life measures. A total of 219 patients were

treated (pregabalin 110, placebo 109). The primary out-

come result was negative: a mean pain score at baseline of

Management of Central Post-Stroke Pain

6.5 in the pregabalin group and 6.3 in the placebo group

reduced at endpoint to 4.9 and 5.0, respectively

(p = 0.578).

However, the result should be cautiously interpreted.

Although the primary endpoint was not met with statistical

significance, pregabalin produced significantly greater pain

relief up to 8 weeks versus placebo, and no loss of pain

reduction was seen thereafter. The negative result was

primarily attributed to the continuous pain reductions over

time in the placebo group, which resulted in the loss of

statistical separation between the two groups at endpoint.

This high placebo effect in pain studies may preclude a

positive outcome of possible efficacious treatments. It has

been shown in previous trials that the higher the effect

during placebo treatment, the higher the number-needed-

to-treat value [82]. Moreover, large pain reductions in the

placebo treatment period may cause a ceiling effect, and it

may be difficult to show the genuine efficacy of a tested

drug [82]. Evidence from other trials suggests a tendency

for the placebo response to increase in magnitude with a

longer study duration [83]. Factors influencing placebo

responses are symptomatic variations, expectation of the

patients, conditioning, and environmental factors [83–85].

These issues have caused debates regarding the optimal

trial design for pain medication. In addition, unlike the

previous studies [59, 69], various medications for CPSP

such as amitriptyline were allowed in this study for ethical

reasons, which may have reduced the room for improve-

ment with pregabalin.

Despite the negative primary result, treatment with

pregabalin resulted in significant improvements in the

secondary endpoints that included sleep disturbances,

anxiety, and the clinician global impression of change.

These results suggest some utility of pregabalin in the

management of CPSP. Adverse events including somno-

lence and peripheral edema were more frequent with pre-

gabalin than with placebo and caused discontinuation of

medication in 8 % of pregabalin-treated patients versus

4 % of placebo-treated patients. However, pregabalin was

generally well tolerated.

4.1.3 Opioids

In a double-blind, placebo-controlled, crossover study,

intravenous infusion of morphine was partially efficacious

in treating central pain (it reduced only brush-induced

allodynia) [86]. Although oral levorphanol was generally

effective in patients with central pain when a high dose was

used (8.9 mg/day), the effect was not significant in patients

with CPSP [87]. Naloxone was not found to be effective in

patients with CPSP [88].

4.1.4 Other Miscellaneous Drugs

Intrathecal baclofen was found to reduce central pain

from various causes, including stroke [89, 90], without

inducing significant side effects. However, oral baclofen

administration up to 60 mg/day was not effective for

central pain [88]. In a double-blind, placebo-controlled,

crossover study, intravenous lidocaine infusion (5 mg/kg

over 30 min) effectively reduced pain scores in 16

patients with central pain due either to stroke or spinal

cord injury [91]. Ketamine, a noncompetitive NMDA

blocker, also reduced pain scores in patients with central

pain due to cord injury [92]. However, the oral NMDA

channel blocker dextromethorphan was less effective [93].

Ziconotide, a novel 25-amino acid peptide derived from

the venom of the genus Conus (poisonous snails) [94], is

effective in chronic pain, including neuropathic pain [95–

98]. The agent is thought to exert its anti-nociceptive

properties by binding to and directly blocking voltage-

sensitive calcium channels without interfacing with opioid

receptors [94]. Although long-term experience with

ziconotide is limited, tolerance problems and dependence,

as found with opioids, do not occur [99]. Unfortunately,

this agent is only effective via intrathecal delivery, and

the invasive administration method is a limitation in the

long-term management of CPSP. Finally, the anti-

arrhythmic mexiletine occasionally produces pain-reliev-

ing effects when co-administered with antidepressants

[72].

4.2 Non-pharmacological Treatment

4.2.1 Surgical Operation

Various surgical procedures have been reported to reduce

central pain; these include rhizotomy [100], sympathec-

tomy [16], dorsal root entry zone lesions [101], cordotomy

[100], thalamotomy [2], postcentral gyrectomy [16, 102],

frontal lobotomy and cingulotomy [16, 103], and hypoph-

ysectomy [104–106]. These procedures are associated with

significant side effects, and their efficacies have not been

examined in controlled trials. To reduce morbidity, radio-

surgical hypophysectomy using a 200–250 Gy maximum

irradiation was introduced [105]. According to a review of

24 patients with thalamic pain who underwent pituitary

radiosurgery, significant pain reduction was achieved in 17

patients (71 %). However, pain recurred within 6 months

in most cases and ten patients (42 %) developed side

effects such as hormonal deficiency [106]. Thus, these

surgical or radiosurgical therapies are not currently

recommended.

J. S. Kim

4.2.2 Stimulation Therapy

Transcutaneous electrical nerve stimulation, or acupunc-

ture, has been reported to benefit some patients with CPSP

[107]. However, the improvement is not observed in many

patients and the effect is usually temporary.

Deep brain stimulation (DBS) with electrodes implanted

within the periventricular gray matter, the specific sensory

thalamic nuclei, or the internal capsule was found to be

effective in selected patients with medically intractable

pain. However, the treatment response of DBS for CPSP is

quite variable among patients and is generally less satis-

factory than for peripheral origin pain [108, 109].

Electrical motor cortex stimulation (MCS) has been

reported to relieve pain in some patients with CPSP [110].

The theoretical basis for this strategy is the inhibition of

nociceptive ascending pathways by MCS observed in

experimental animals. The success rates are reported to

range from 0 to 67 % (average 52 %) [111], and there are

occasional peri-operative complications such as seizures,

subdural hematoma, and infection [104, 112]. The loss of

efficacy at long-term follow-up was observed in some

patients. Unfortunately, controlled studies showing the

efficacy of MCS are rare. Recent reviews have shown that

MCS is less efficacious for CPSP than for peripheral neu-

ropathic pain [112, 113]. DBS and MCS are not currently

recommended and may be reserved as a last resort method

for medically intractable patients in the setting of a well

established, functional neurosurgery center.

More recently, a less invasive high-frequency repetitive

transcranial magnetic stimulation (rTMS) of the motor

cortical area was shown to provide modest and short-

lasting effects on neuropathic pain [114]. Hosomi et al.

[115] conducted a randomized, double-blind, sham-con-

trolled, crossover study using rTMS. A series of ten daily

5-Hz rTMS sessions (500 pulses/session) of the primary

motor cortex or sham stimulation was applied to 64

patients (81 % of whom had CPSP; 29 in the rTMS group

and 35 in the sham group). The primary outcome was

short-term pain relief assessed using a visual analog scale.

The real rTMS induced greater reductions in the visual

analog scale than sham (p \ 0.001). The mean reduction

rates of the visual analog scale of ten averaged sessions in

the rTMS and sham groups were 6.51 and 2.44 %,

respectively, just after stimulation, and 3.38 versus

0.66 %, respectively, 60 min after stimulation. No serious

adverse events were observed. These findings suggest the

efficacy and tolerability of high-frequency rTMS of the

motor cortex. However, this effect is transient, modest,

and varies among individuals. Nevertheless, repeated

daily rTMS may be administered in selected patients who

do not respond to medical therapy and experience suc-

cessful pain relief in initial rTMS treatments. There is a

need for larger, rigorously designed studies, particularly

of longer courses of stimulation [116].

4.2.3 Cognitive-Behavioral Therapy

Chronic neuropathic pain is often associated with comorbid

conditions such as depression, anxiety, and sleep distur-

bances that affect daily functioning and overall quality of

life. It is argued that cognitive-behavioral therapy (CBT)

may be suitable as an adjunct to traditional biomedical

interventions. However, well designed studies evaluating

the effectiveness of CBT for the management of neuro-

pathic pain are rare [117]. A recent, randomized, controlled

study using patients with neuropathic pain due to spinal

cord injury showed that CBT reduced anxiety and

increased participation in activities, but the effect on the

reduction of pain was not unequivocally documented [118].

Studies for CPSP are not yet available, and no conclusions

can currently be drawn on the efficacy of CBT for CPSP

patients.

5 Current Treatment Approaches

Research supporting the effectiveness of pharmacological

treatment is insufficient, and there are no head-to-head

trials comparing different medications for CPSP [28].

Therefore, there are no universally accepted guidelines.

This section describes the typical approach used to treat

CPSP patients in the Department of Neurology, Asan

Medical Center (Fig. 1).

Currently, for the management of CPSP, we start with

amitriptyline because there is sufficient evidence and

Amitriptyline(up to 100 mg/d)

Lamotrigine(up to 400 mg/d)

Gabapentin (up to 2400 mg/d)or Pregabalin (up to 600 mg/d)

Combination (antiadrenergics +

antiepileptics)

Alternative choices

Nortriptyline, Carbamazepine, Clonazepam, Zonisamide, Fluvoxamine, Levorphanol, Mexiletine , Transcranial motor cortex stimulation

Fig. 1 Diagram showing the current treatment strategy for central

post-stroke pain at Asan Medical Center

Management of Central Post-Stroke Pain

expert experience supporting that this drug is effective.

Moreover, amitriptyline is cheap and easily available.

However, side effects are relatively common and should be

carefully monitored, especially in older patients. We start

with 10 mg/day and increase the dosage to the highest dose

that is tolerated (generally up to 100 mg/day). If the drug is

inefficient or not tolerated, similar drugs such as nortrip-

tyline may be used. If sufficient pain relief is not achieved,

we use antiepileptics, first lamotrigine up to 400 mg/day,

again with monitoring of side effects. If inefficient or not

tolerated, other antiepileptics such as carbamazepine, val-

proic acid, or clonazepam may be tried, even if they have

not been proven to be effective in CPSP.

Gabapentin and pregabalin are nowadays increasingly

used, even though they are not solidly proven to be

effective for CPSP. They are tolerable, safe, and effective

for treating a broad range of neuropathic pain, including

central pain due to spinal cord injury. These agents may be

used if amitriptyline and lamotrigine are not effective.

Some consider gabapentin or pregabalin to be a second-line

drug and try one of them if the efficacy of amitriptyline is

unsatisfactory. Because pregabalin improves CPSP-related

anxiety or sleep disturbances [81], it may be particularly

beneficial in patients with these problems.

If the therapeutic response is not sufficient with mono-

therapy, a combined medication may be considered, such

as adrenergic antidepressants plus antiepileptics. In patients

with peripheral neuropathic pain, a combination of nor-

triptyline and gabapentin at maximum tolerated doses

produced significantly greater pain relief than when either

drug was administered alone [119]. There were no serious

adverse effects. Therefore, combined medication may also

be effective in CPSP patients. However, one should be

wary of side effects, which are likely to be more common

and serious in patients with stroke than in those with

peripheral diseases. Finally, other potentially effective

drugs such as fluvoxamine or mexiletine may be adjunc-

tively tried, according to the physician’s experience.

We believe that it is important to increase the dosage of

a drug to the maximum tolerated dosage before switching

to or adding another drug. This is partly because a drug

effect may be observed only when a very high dosage is

used and partly because there are only a few drugs that are

proven to be effective for CPSP. In this sense, patience is

needed for both physicians and patients. It would be

advisable to simultaneously manage related problems that

can aggravate pain, such as depression, anxiety, and sleep

disturbances. In patients with these behavioral problems,

CBT may be used, on the basis of the data of patients with

neuropathic pain due to spinal cord injury [118]. Until

more data are obtained, non-pharmacological therapies

should be reserved only for medically intractable cases and

be performed in centers with sufficient experience.

Additionally, they may be performed as an experimental

trial, under rigorous control from experts and research

institutes.

6 Conclusions and Future Directions

Although CPSP has long been recognized in the medical

literature, it has received relatively little attention. With the

high prevalence of stroke patients and ever-increasing

older population worldwide, we must pay more attention to

this issue. As described herein, the treatment of CPSP is

still unsatisfactory and only a few well designed and con-

trolled drug studies are available (Table 1). There are

various reasons for the paucity of therapeutic investiga-

tions. First, the prevalence of CPSP among stroke patients

is low; each physician typically sees only a small number

of CPSP patients. Moreover, because the onset of CPSP is

often delayed, patients who are referred to smaller clinics

in the chronic stage may be insufficiently assessed.

Therefore, it is difficult to recruit a large number of CPSP

patients. Second, drug companies are generally interested

in more common pain disorders, such as root or peripheral

nerve diseases, than relatively rare CPSP syndromes. With

difficulties in recruiting a large number of patients, high

placebo effects, and the belief that therapeutic success is

more often achieved in peripheral rather than central neu-

ropathic pain syndromes, pharmaceutical companies are

less enthusiastic about performing large-scale clinical trials

for CPSP.

Nevertheless, given the magnitude of the problem, fur-

ther trials should be performed. Future studies may have to

consider ways to reduce or modulate the confounding

placebo effect and the potential benefits and hazards of

combination therapy. Considering the heterogeneous

symptoms of CPSP, the pathogenesis may not be identical

in each patient. Therefore, some drugs may be effective

only for certain types of pain (e.g., burning vs. cold sen-

sations, continuous vs. intermittent). Likewise, given the

diverse comorbid conditions associated with CPSP, certain

therapies may be more effective in patients with certain

comorbid conditions. Studies focusing on these issues are

needed. The characteristics of patients who respond well to

non-pharmacological therapies such as transcranial stimu-

lation or CBT should also be identified. Undoubtedly,

robust basic studies should be performed to more clearly

elucidate the pathogenic mechanism of CPSP. With

improved understanding of the pathophysiology and

focused clinical trials, we may develop better treatment

strategies for CPSP.

Acknowledgments No sources of funding were used to support the

writing of this manuscript.

J. S. Kim

Conflict of interest J.S. Kim has no conflicts of interest.

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Management of Central Post-Stroke Pain