-

VOL XXI • NO 1 • JUNE 2013

®

Editorial Board

Editor-in-Chief

JaneÊC.ÊBallantyne,ÊMD,ÊFRCAAnesthesiology,ÊPainÊMedicineUSA

AdvisoryÊBoard

MichaelÊJ.ÊCousins,ÊMD,ÊDSCPainÊMedicine,ÊPalliativeÊMedicineAustralia

PsychosocialÊAspectsÊofÊChronicÊPelvicÊPain

Vol.ÊXXI,ÊIssueÊ1Ê JuneÊ2013

Pain is unwanted, is unfortunately common, and remains essential for survival (i.e., evading danger) and facilitating medical diagnoses. This complex amalgamation of sensation, emotions, and thoughts manifests itself as pain behavior. Pain is a moti-vating factor for physician consultations1 and for emergency department visits and is

PAIN: CLINICAL UPDATES • SEPTEMBER 2015 1

VOL XXIII • NO 5 • SEPTEMBER 2015

Neurostimulation for Neuropathic Pain: Outcomes and New Paradigms

Srinivasa N. Raja, MDDepartment of Anesthesiology and Critical Care MedicineJohns Hopkins UniversityBaltimore, Md., USAEmail: sraja2@jhmi.edu

Mark Wallace, MDDepartment of AnesthesiologyUniversity of CaliforniaSan Diego, Calif., USAEmail: mswallace@ucsd.edu

Neuropathic pain afflicts

millions of people glob-

ally and presents a major

health and economic bur-

den. Epidemiological studies carried out

with validated screening tools estimate

that as many as 7–8% of adults in the

general population have pain with neu-

ropathic characteristics.47 Neuropathic

pain can result from various etiologies,

such as traumatic or surgical injuries to

peripheral nerves, infectious diseases

(e.g., herpes zoster, HIV, or leprosy),

metabolic disorders, cancer and its

treatment, and injuries or diseases that

affect the central nervous system (e.g.,

stroke or spinal cord injury). Nearly a

fourth of people with chronic diabetes

have neuropathic pain—a worldwide

estimate of nearly 50 million indi-

viduals. Moreover, neuropathic pain is

reported to be more severe than non-

neuropathic pain and can dramatically

affect health-related quality of life.43

Several evidence-based recom-

mendations for pharmacological

treatments have been published,

including a recently updated NeuPSIG

recommendation based on a systematic

review and meta-analysis of published

and unpublished clinical trials.15 Data

from these studies suggest that the

management of patients with chronic

neuropathic pain is challenging, with

more than 50% of patients experiencing

only partial or no relief of their pain. In

addition, the adverse effects associated

with the drugs used to manage the pain

may limit their clinical utility, particu-

larly in the elderly population. Hence,

experts are increasingly considering

interventional therapies such as nerve

blocks and neuromodulatory strategies

for patients with refractory neuropathic

pain and those who are intolerant to

systemic drugs. On the basis of the

available evidence from clinical trials,

NeuPSIG published recommendations in

2013 regarding the use of interventional

therapies for neuropathic pain.14 Sev-

eral more recent studies have provided

additional evidence for the role of

neurostimulation therapies in the man-

agement of neuropathic pain.13 This

issue of Pain: Clinical Updates reviews

the latest evidence for emerging neuro-

stimulation therapies that may provide

alternative therapeutic strategies for

patients with neuropathic pain.

Spinal Cord Stimulation

Spinal cord stimulation (SCS) as a

therapy for chronic pain was intro-

duced nearly half a century ago by

Norman Shealy and colleagues. Recent

advances in percutaneous implantation

techniques and devices, technological

advances in stimulation electrodes, in-

novations in implantable pulse gen-

erators, and the introduction of novel

stimulation parameters have resulted in

a surge in the use of implantable thera-

pies. The relative safety and reversibil-

ity of this treatment modality, as well as

its cost-effectiveness over the long term,

have made it an attractive strategy for

managing patients with refractory,

chronic neuropathic pain. Although

SCS has been used to treat a variety of

neuropathic pain states, controlled trials

have shown the best evidence for long-

term efficacy in patients with failed back

surgery syndrome (FBSS) and complex

regional pain syndrome (CRPS) type I,

and more recently in diabetic neuro-

pathic pain. Based on the GRADE cri-

teria, a NeuPSIG consensus group rated

the quality of evidence from clinical

trials as moderate, and gave it a “weak”

recommendation for use in FBSS with

radiculopathy and CRPS.14 Although the

same report considered the evidence for

the efficacy of SCS in diabetic neuro-

pathic pain to be low and labeled its

PAIN: CLINICAL UPDATES • SEPTEMBER 20152

recommendation as “inconclusive,” more

recent controlled trials provide addi-

tional evidence for its efficacy.

Stimulation Paradigms

Conventional SCS that is associated with

a paresthesia uses a monophasic, square-

wave pulse at a frequency in the 40–80-

Hz range. In an attempt to improve suc-

cess and avoid some of the undesirable

side effects of SCS, some physicians are

using new stimulation parameters, such

as burst and high-frequency SCS (Fig. 1).

Recent studies examining the long-term

effectiveness of these strategies provide

encouraging observations that should be

confirmed by additional controlled trials.

Traditional SCS

Whereas burst and high-frequency

stimulation use fixed wave parameters,

traditional SCS adjusts the different pa-

rameters to achieve fiber depolarization

and paresthesias that overlap the pain-

ful area. Parameters that can be adjust-

ed include electrode polarity, amplitude,

pulse width, and frequency. Electrode

polarity controls the shape and density

of the electrical field, as determined by

the distance between the electrodes

and the number of positive versus

negative electrodes used. The amplitude

is the strength of the stimulation pulse.

Measured in volts or milliamps, it is the

primary control over the intensity of

the sensation. Higher amplitudes will

ultimately result in painful stimula-

tions. The highest amplitude that can be

achieved with current devices is 15 V.

The pulse width is the amount of time

the stimulation pulse lasts and is mea-

sured in microseconds. Higher (wider)

settings will cause the stimulation field

to “stay on” longer and depolarize both

large- and small-diameter fibers. Lower

pulse width will narrow the stimula-

tion, resulting in mostly large-fiber

depolarization. Typical clinically used

pulse widths range from 175 to 600 µs

but can go as high as 1000 µs. Frequen-

cy is the number of stimulation pulses

delivered per second. The frequency of

traditional SCS can be as high as 1200

Hz. Increasing the frequency boosts the

number of action potentials generated

by the nerve. Changes in frequency

produce a change in sensation from

pulsing (low) to fluttering (high). Higher

frequencies dramatically affect battery

consumption.

Burst SCS

Burst stimulation consists of closely

spaced, high-frequency stimuli

delivered to the spinal cord (Fig. 1).

The stimulus paradigm consists of a

40-Hz burst mode of constant-current

stimuli with 5 spikes at 500 Hz per

burst and pulse width and interspike

intervals of 1 ms. A possible advan-

tage of this stimulus paradigm is

that it does not cause paresthesia in

the painful region. In a randomized

controlled trial (RCT), burst stimula-

tion was able to improve back, limb,

and general pain by 51%, 53%, and

55%, respectively, compared to 30%,

52%, and 31% with tonic stimulation.

Similar significant improvements in

pain now, least pain, and worst pain

were observed with burst stimulation.

The differences between tonic and

burst stimulation could be due to more

selective modulation of the medial

pain pathways by burst stimulation, as

evidenced by activation of the dorsal

anterior cingulate cortex.9 More recent

retrospective analysis of patients who

were switched from tonic to burst

stimulation suggests that the latter

can rescue a proportion of those who

Fig. 1. Spinal cord stimulation waveforms.

PAIN: CLINICAL UPDATES • SEPTEMBER 2013 3

do not respond to tonic stimulation

and improve pain reduction in those

who do.8 Additional RCTs are needed

to confirm these observations

High-Frequency Stimulation

High-frequency stimulation uses fre-

quencies up to 10 kHz. Although the

currently available device is capable

of amplitudes up to 15V and a pulse

width up to 1000 ms, newer devices

reach 10 KHz with amplitudes of 1

to 5 mA and very low pulse width,

resulting in paresthesia-free stimula-

tion. The exact mechanism of pain

relief is unclear, but preclinical studies

have shown that a high-frequency,

alternating-current sinusoidal

waveform applied to a nerve results

in reversible block of activity.1 This

block occurs in three phases: an onset

response, a period of asynchronous

firing, and a steady state of complete

or partial block. This technology is

currently available in Europe and

Australia and recently received ap-

proval in the United States. Because of

the high frequencies used, the device

requires a rechargeable battery to

support the high power consumption.

It is used primarily to treat back pain

but has some effect on lower-extremi-

ty pain. Leads are placed anatomically

over T9 in the midline; intraoperative

paresthesia mapping is not

necessary, thus shorten-

ing procedure time. A U.S.

pilot study in 24 patients

demonstrated a significant

reduction in back and leg

pain.42 A European study

was conducted in 83 pa-

tients with primarily low-

back pain. Seventy-two

subjects had a successful

trial. Long-term follow-up

to 12 months showed a sig-

nificant reduction in both

back and leg pain. The

study also reported signifi-

cant improvements in the

average Oswestry Dis-

ability Index score and in

sleep disturbance, as well

as high patient satisfac-

tion.45 An ongoing clinical

trial in the United States

of subjects who have low

back pain with or without

lower-extremity pain is

testing an SCS device that

provides both traditional

and high-frequency SCS

(the ACCELERATE Trial).

Complex Regional Pain Syndrome

CRPS is a well-established indication for

SCS, for which it is approved by the U.S.

Food and Drug Administration (FDA).

The primary evidence for effective-

ness of SCS in CRPS patients is based

on a prospective, randomized trial of

54 patients followed for up to 5 years.

Kemler and coworkers20 randomized

CRPS type I patients in a 2:1 ratio to two

groups: SCS with physical therapy or

physical therapy alone. Two-thirds of

the 24 patients in the SCS group were

implanted with devices after a success-

ful trial stimulation. Pain was reduced

by 2.4 cm on a 10-cm visual analogue

scale (VAS) in the SCS group, whereas

Fig. 2. Spinal cord stimulation (SCS) for diabetic neuropathic pain. (a) Average pain scores (VAS) for the SCS treatment group (dark gray) and control group (light gray) at baseline and after 1, 3, and 6 months of treatment; a high score corresponds with severe pain. (b) Average McGill Pain Questionnaire (MPQ) Qual-ity of Life scores; a high score corresponds with severely disturbed daily activities and sleep. Error bars represent standard deviation. From de Vos et al.11

PAIN: CLINICAL UPDATES • SEPTEMBER 20154

it increased by 0.2 cm in the physical

therapy group. Moreover, 39% of SCS

patients, compared to 6% of control

patients, rated themselves as “much

improved.” The observed beneficial

effects in the SCS group persisted at 2

years,22 but subsequent evaluations at

3–5-year follow-ups failed to demon-

strate differences in outcome between

the groups.23 Despite a 42% reopera-

tion rate in the SCS patients during the

5-year study, 95% of the patients who

received SCS indicated that they would

repeat the procedure.21 Other retrospec-

tive and prospective case series also

have reported reduced pain, improved

function, and reduced medication use

after SCS in CRPS patients. An indepen-

dent systematic review of the studies

concluded that SCS showed evidence for

efficacy relative to conventional medical

management in patients with CRPS type

I.38 Both NeuPSIG and the European

Federation of Neurological Societies

(EFNS) gave a weak recommendation

for use of SCS in CRPS type I, on the

basis of the moderate evidence.6,14

Failed Back Surgery Syndrome

Two published RCTs, along with several

long-term outcome case series, support

the use of SCS for FBSS. Most studies

evaluated the effects of SCS in patients

who had treatment-refractory FBSS

with prominent radicular symptoms. In

the first RCT, North et al.33 studied 50

patients who had undergone previous

spinal surgeries and were candidates

for reoperation to alleviate chronic pain

that was more bothersome in their legs

than their back. Patients were random-

ized to either treatment with SCS or

reoperation, but they were allowed to

cross over to the other treatment if dis-

satisfied with the results of their first

treatment. The criterion for “success”

was patient satisfaction with treat-

ment and a 50% or greater reduction

in pain. Among 45 patients available

for evaluation approximately 3 years

postoperatively, the authors reported

a successful outcome in 47% of SCS

patients versus 11.5% of the reoperation

patients. The rate of crossover to alter-

native treatment was also significantly

lower in the SCS patients (~20%) than

in the reoperation patients (>50%).

In the second, larger RCT, 100

FBSS patients with more severe leg

pain than back pain were randomized

to conventional medical management

(CMM) alone or CMM with SCS.27 The

primary outcome measure was the re-

sponder rate (the proportion of patients

obtaining at least 50% relief of leg pain)

at 6 months, after which patients were

allowed to cross over. In the 88 patients

available for analysis, SCS was success-

ful in 48% and 34% at 6 and 12 months,

respectively, in contrast to 9% and 7%

in the CMM group. More than 50% of

subjects originally assigned to CMM

crossed over to receive SCS, whereas

only 18% of SCS patients crossed over

to CMM. Although the total health care

cost in the SCS group was significantly

higher, subjects in the SCS group expe-

rienced significantly improved quality

of life and functional capacity, as well

as greater treatment satisfaction than

those in the CMM group.31 Device-

related reoperation is a concern, as 31%

of the SCS patients available for follow-

up at 2 years had required surgical

revision. Considering the strengths and

limitations of these trials, the authors

of a systematic review concluded that

SCS appears to be more effective than

CMM and reoperation.38 Both NeuPSIG

and the EFNS gave SCS a weak recom-

mendation for FBSS.6,14 Because of the

invasiveness of the procedure, the risk

of complications, and the relatively

low response rate to SCS, the NeuPSIG

recommendation was to reserve SCS

for patients who do not respond to less

invasive treatment options, includ-

ing consideration of a trial of epidural

steroid injections.

In a recent observational study of

48 patients, burst stimulation led to a

significant additional pain reduction

of approximately 28% in patients with

FBSS, compared to that in patients

who received conventional tonic

stimulation.10

Painful Diabetic Neuropathy

Earlier small, prospective observational

trials evaluating the effects of SCS on

pain in patients with refractory painful

diabetic neuropathy (PDN) reported

substantial benefits, although the

complication rate was 33% in one of the

trials.7,12 Two RCTs of SCS in patients

with PDN reported in 2014 provide ad-

ditional evidence for the effectiveness

of SCS in the management of PDN. In a

multicenter randomized trial, 36 PDN

patients with severe lower-limb pain

refractory to conventional therapy

were randomized to receive either SCS

in combination with the best medical

treatment (SCS group, n = 22) or medi-

cal treatment alone (BMT group, n =

14).39 Treatment success, determined

at 6 months, was defined as ≥50% pain

relief or “(very) much improved” for

pain and sleep on the Patient Global

Impression of Change scale.

Treatment success was observed

in 59% of patients in the SCS group

compared to 7% in the BMT group. SCS

was not without risk in this population,

as one SCS patient died of a subdural

hematoma. In a second, larger, multi-

center controlled trial, 60 PDN patients

were similarly randomized in a 2:1 ratio

to receive best conventional medical

practice with (SCS group) or without

(control group) additional SCS therapy.11

After 6 months of treatment, average

pain scores decreased significantly

from 73 to 31 (0–100 VAS) in the SCS

PAIN: CLINICAL UPDATES • SEPTEMBER 2013 5

group, but remained unchanged at 67

in the control group (Fig. 2). Improve-

ments in quality of life measures were

also observed. In a recent observational

study that compared conventional

tonic stimulation with burst stimula-

tion, the latter led to a significant ad-

ditional 44% pain reduction on average

in patients with PDN.10

Other Neuropathic Pain States

SCS is used to treat several other neuro-

pathic pain states, such as post-amputa-

tion stump and phantom pains, posther-

petic neuralgia, spinal cord injury, and

other traumatic peripheral neuralgias.

The evidence for effectiveness of SCS in

these pain states has not been carefully

evaluated in controlled trials and is

based primarily on observational studies

in small groups of subjects.

Predictors of Success

The success of SCS for neuropathic pain

may depend on appropriate patient

selection. Psychological traits may play

an important role in modeling individ-

ual differences in the pain experience.

Hence, psychological screening might

be useful in helping to predict which

patients are likely to benefit from SCS.4

In addition, preliminary studies suggest

that quantitative sensory testing may

help physicians determine the sensory

phenotype and the mechanism of pain

in patients with neuropathic pain as

well as their responses to SCS.3 Studies

are needed to further explore whether

strict patient selection based on psycho-

logical and sensory profiles can reduce

the failure rate of SCS.

Peripheral Nerve/Field Stimulation

Peripheral nerve stimulation (PNS),

first described nearly 50 years ago, has

recently become more attractive after

the development of a percutaneous

technique.48,49 PNS has been used for

a variety of chronic neuropathic pain

states, such as postsurgical neuralgias,

post-traumatic neuralgia, occipital

neuralgia, and postherpetic neuralgia

(for review see Petersen and Slavin36).

PNS has also been used to alleviate a

variety of headaches, including chronic

daily headaches, cluster headaches, and

migraine, and to treat CRPS. Most stud-

ies reporting benefits of PNS have been

uncontrolled case series. A random-

ized, double-blind, controlled trial of

occipital nerve PNS for migraine failed

to meet its primary endpoint (difference

in responders, defined as patients who

achieved a ≥50% reduction in mean dai-

ly VAS scores).37 However, the authors

did find significant reductions in pain,

headache days, and migraine-related

disability. Peripheral nerve field stimu-

lation in the region of maximal pain

has also been used alone or in combina-

tion with SCS, particularly for chronic

axial low back pain.2,24 Although the

devices used for PNS are “off-label” in

the United States, they are approved in

Europe for the treatment of intractable

migraine and chronic low back pain.

Dorsal Root Ganglion Stimulation

Although traditional SCS has shown

effectiveness in certain pain states,

reports suggest that 30–40% of patients

fail to achieve adequate pain relief or

experience a reduction in effective-

ness with time. Recently, the dorsal

root ganglion (DRG) has emerged as

a potential target for treating chronic

neuropathic pain 26. Experts hypoth-

esize that, relative to traditional SCS,

stimulation of sensory neurons in the

DRG may result in more precise and

selective stimulation, thereby reduc-

ing unwanted side effects observed

with traditional SCS.25 Some authors

postulate that DRG stimulation may be

Editorial Board

Editor-in-Chief

Jane C. Ballantyne, MD, FRCAAnesthesiology, Pain Medicine

USA

Advisory Board

Michael J. Cousins, MD, DSCPain Medicine, Palliative Medicine

Australia

Maria Adele Giamberardino, MDInternal Medicine, Physiology

Italy

Robert N. Jamison, PhDPsychology, Pain Assessment

USA

Patricia A. McGrath, PhDPsychology, Pediatric Pain

Canada

M.R. Rajagopal, MDPain Medicine, Palliative Medicine

India

Maree T. Smith, PhDPharmacology

Australia

Claudia Sommer, MDNeurologyGermany

Harriët M. Wittink, PhD, PTPhysical TherapyThe Netherlands

PublishingDaniel J. Levin, Publications Director

Elizabeth Endres, Consulting Editor

Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the find-ings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily reflect those of IASP or of the Officers or Councilors. No responsibility is as-sumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas con-tained in the material herein.

Because of the rapid advances in the medical sciences, the publisher recommends independent verification of diagnoses and drug dosages.

© Copyright 2015 International Association for the Study of Pain. All rights reserved.

For permission to reprint or translatethis article, contact:

International Associationfor the Study of Pain

1510 H Street NW, Suite 600,Washington, D.C. 20005-1020, USA

Tel: +1-202-524-5300Fax: +1-202-524-5301

Email: iaspdesk@iasp-pain.orgwww.iasp-pain.org

PAIN: CLINICAL UPDATES • SEPTEMBER 20156

or CRPS. The study’s results, which will

include safety and efficacy endpoints

and responder rate analysis, may help to

determine the efficacy of DRG stimula-

tion in this population.

Motor Cortex and Noninvasive Brain Stimulation

Motor cortex stimulation is based on

an observation nearly 25 years ago

by Tsubokawa et al.44 that stimulation

of the precentral gyrus below motor

threshold relieves pain in patients with

thalamic pain. A number of subsequent

clinical observations have shown ef-

ficacy in trigeminal neuropathic pain

and deafferentation syndromes such as

poststroke pain and pain resulting from

spinal cord injury or brachial plexus in-

juries (for reviews see Sukul and Slavin41

and Moore et al.32). Although more than

50% of patients appear to respond to

motor cortex stimulation during the

first few months, the pain relief may

wane over longer periods of time.17,40

Noninvasive brain stimulation

techniques include repetitive tran-

scranial magnetic stimulation (rTMS),

transcranial direct current stimula-

tion (tDCS), cranial electrotherapy

stimulation (CES), and reduced imped-

ance noninvasive cortical stimula-

tion (RINCE; for recent reviews, see

O’Connell et al.35 and Young et al.50).

In contrast to conventional electrical

stimulation that is likely to reach only

the most superficial layers of the cortex,

the magnetic field created by rTMS

passes through the scalp and cranium

to excite or inhibit various cortical and

subcortical neural networks. Similar

to other neuromodulation techniques,

the effects of rTMS may depend on the

positioning of the coil and its orientation

to the underlying brain structures, the

particularly beneficial when the pain

distribution is in a region over which

paresthesia is difficult to achieve with

conventional SCS. (Fig. 3)29,30 In a multi-

center, prospective, observational cohort

study, 32 of 51 subjects with chronic neu-

ropathic pain (63%) who completed a trial

with a DRG-SCS device were implanted

with permanent devices. Seven of those

subjects had their device removed within

a year, and the other 25 subjects were

followed up to a year.30 The 56% pain

reduction and 60% responder rate (>50%

reduction in overall pain) reported by

the authors are promising results, but

they should be interpreted with caution

owing to the uncontrolled nature of the

study and the method of data analysis

(not intention-to-treat). In addition, the

safety of the procedure needs careful

study, as 86 safety events were reported

in 29 subjects, including temporary

motor stimulation, cerebrospinal fluid

leak and associated headache, infection,

and lead revisions. Similar beneficial

results were observed in a group of

subjects with lower-extremity CRPS

(8 of 11 trialed subjects received device

implants) who were followed for a year.46

Several recent abstracts presented at

the North American Neuromodulation

Society also suggest promising benefits of

DRG stimulation in mixed neuropathic

pain states that are worthy of further

investigation. Huygen et al.18 reported

pooled data from prospective studies in

Europe of 19 patients with upper-limb

neuropathic pain of various etiologies

and showed mean reductions in pain

of 54.6% and 58.6% at 3 and 6 months,

respectively, with concurrent improve-

ments in quality of life.

Recently, 152 patients were enrolled

in a prospective, randomized, multi-

center, controlled trial (ACCURATE

Trial) designed to evaluate the safety

and efficacy of a DRG stimulation device

for treatment of chronic lower-limb

pain caused by nerve injuries (causalgia)

Fig. 3. Lead placement for dorsal root ganglion stimulation.

PAIN: CLINICAL UPDATES • SEPTEMBER 2013 7

stimulation parameters, and the dura-

tion of stimulation. Reviewers postulate

that high-frequency (>5 Hz) stimulation

leads to increased cortical excitability

and a reduction in cortical inhibition,

whereas low-frequency stimulation

(≤1 Hz) causes a transient reduction in

cortical excitability without affecting

cortical inhibition.16 Although several

reports of uncontrolled trials suggest

that rTMS of the motor cortex (M1)

has beneficial effects in various central

and peripheral neuropathic pain states,

results of controlled trials have been

mixed. A recently updated Cochrane

review35 included 56 trials (1710 ran-

domized subjects): 30 studies of rTMS,

11 of CES, 14 of tDCS, and one study

of RINCE. Several studies included a

mixture of central, peripheral, and fa-

cial neuropathic pain states of various

etiologies. The authors concluded that

single doses of high-frequency rTMS of

the motor cortex may have small short-

term effects on chronic pain (12%; 95% CI,

8–15%). In addition, multiple-dose studies

failed to consistently demonstrate effec-

tiveness, and low-frequency rTMS, rTMS

applied to the prefrontal cortex, CES, and

tDCS were ineffective in the treatment of

chronic pain. The primary advantage of

these techniques is their excellent safety

profile, but the evidence for efficacy is in-

conclusive and the magnitude of benefi-

cial effects failed to meet the threshold of

minimal clinical significance (≥15%) in the

systematic review. Some have suggested

that rTMS can be used as a complemen-

tary therapy in patients with chronic

refractory neuropathic pain syndromes.

50 A recent evidence-based guideline

concluded that “there is a sufficient

body of evidence to accept with level A

(definite efficacy) the analgesic effect of

high-frequency (HF) rTMS of the pri-

mary motor cortex (M1) contralateral to

the pain.”28 Relative contraindications of

TMS include a history of epilepsy and

the presence of aneurysm clips, deep

brain electrodes, and cochlear implants.

Deep Brain Stimulation

Deep brain stimulation (DBS) is an

accepted treatment for disorders like

Parkinson’s disease that are associ-

ated with motor signs such as rigidity,

bradykinesis, and tremor. The use of

chronic intracranial stimulation for

pain, however, remains controversial.

Various DBS sites, including the inter-

nal capsule, various nuclei in the sen-

sory thalamus, the periaqueductal and

periventricular gray, the motor cortex,

septum, nucleus accumbens, posterior

hypothalamus, and anterior cingulate

cortex, have been examined as poten-

tial brain targets for pain control. The

effectiveness of DBS has been the sub-

ject of case series in diverse etiologies

of chronic pain, but results have been

inconsistent. Two multicenter trials

of DBS for chronic pain conducted in

the 1990s failed to demonstrate long-

term beneficial effects.5 Thus, current

evidence is inconclusive for determin-

ing the role of DBS in the treatment of

neuropathic pain. Ongoing, better-con-

trolled trials may shed more light on

its role as a therapeutic alternative (see

review by Keifer et al.19 for details).

Conclusions

The clinical literature now spans more

than three decades on the clinical

use of spinal cord stimulation to treat

chronic neuropathic pain. Although

the evidence is “weak” on the efficacy

of this important therapy, this does not

imply that it is not an effective therapy.

The “weak” evidence is not the result of

failed trials but rather a consequence of

difficulties in successfully conducting

controlled clinical trials with interven-

tional therapies.34 This problem stresses

the need for alternative methods such

as large registries to study the indi-

cations and clinical benefits of this

important therapy. Nonetheless, more

recent, well-conducted studies support

both the efficacy and cost-effectiveness

of this therapy in several neuropathic

pain syndromes.

Although SCS has dominated the

field of stimulation over the past three

decades, improvements in SCS technol-

ogy as well as new stimulation thera-

pies are emerging that should prove to

be an important addition to our stimu-

lation armamentarium. These new

therapies are not likely to replace SCS,

but rather will supplement it or treat

patients not responsive to traditional

SCS. By expanding the horizon of stim-

ulation techniques, we will continue to

successfully treat an increasing propor-

tion of neuropathic pain patients who

currently have limited options.

References

1. Bhadra N, Kilgore KL. High-frequency electrical conduction block of mam-malian peripheral motor nerve. Muscle Nerve 2005;32:782–90.

2. Bernstein CA, Paicius RM, Barkow SH, Lempert-Cohen C. Spinal cord stim-ulation in conjunction with peripheral nerve field stimulation for the treat-ment of low back and leg pain: a case series. Neuromodulation 2008;11:116–23.

3. Campbell CM, Buenaver LF, Raja SN, Kiley KB, Swedberg LJ, Wacnik PW, Cohen SP, Erdek MA, Williams KA, Christo PJ. Dynamic pain phenotypes are associated with spinal cord stimulation-induced reduction in pain: a repeated measures observational pilot study. Pain Med 2015;16:1349–60. 

4. Campbell CM, Jamison RN, Edwards RR. Psychological screening/phe-notyping as predictors for spinal cord stimulation. Curr Pain Headache Rep 2013;17:307.

5. Coffey RJ. Deep brain stimulation for chronic pain: results of two multi-center trials and a structured review. Pain Med 2001;2:183–92.

6. Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, Simpson BA, Taylor RS. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 2007;14:952–70.

7. Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005;22:393–8.

8. De Ridder D, Lenders MW, De Vos CC, Dijkstra-Schoiten C, Wolters R, Vancamp T, Van Looy P, Van Havenbergh T, Vanneste S. A 2-center compara-tive study on tonic versus burst spinal cord stimulation: amount of responders and amount of pain suppression. Clin J Pain 2015;31:433–7.

9. De Ridder D, Plazier M, Kamerling N, Menovsky T, Vanneste S. Burst spi-nal cord stimulation for limb and back pain. World Neurosurg 2013;80:642–9.

PAIN: CLINICAL UPDATES • SEPTEMBER 20158

10. de Vos CC, Bom MJ, Vanneste S, Lenders MW, de Ridder D. Burst spinal cord stimulation evaluated in patients with failed back surgery syndrome and painful diabetic neuropathy. Neuromodulation 2014;17:152–9.

11. de Vos CC, Meier K, Zaalberg PB, Nijhuis HJA, Duyvendak W, Vesper J, Enggaard TP, Lenders MWPM. Spinal cord stimulation in patients with painful diabetic neuropathy: a multicentre randomized clinical trial. Pain 2014;155:2426–31.

12. de Vos CC, Rajan V, Steenbergen W, van der Aa HE, Buschman HPJ. Effect and safety of spinal cord stimulation for treatment of chronic pain caused by diabetic neuropathy. J Diabetes Complications 2009;23:40–5.

13. Deer TR, Krames E, Mekhail N, Pope J, Leong M, Stanton-Hicks M, Golovac S, Kapural L, Alo K, Anderson J, Foreman RD, Caraway D, Narouze S, Linder-oth B, Buvanendran A, Feler C, Poree L, Lynch P, McJunkin T, Swing T, Staats P, Liem L, Williams K. The appropriate use of neurostimulation: new and evolving neurostimulation therapies and applicable treatment for chronic pain and selected disease states. Neuromodulation 2014;17:599–615.

14. Dworkin RH, O’Connor AB, Kent J, Mackey SC, Raja SN, Stacey BR, Levy RM, Backonja M, Baron R, Harke H, Loeser JD, Treede RD, Turk DC, Wells CD. Interventional management of neuropathic pain: NeuPSIG recommendations. Pain 2013;154:2249–61.

15. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice ASC, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73.

16. Fitzgerald PB, Fountain S, Daskalakis ZJ. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin Neurophysi-ol 2006;117:2584–96.

17. Fontaine D, Hamani C, Lozano A. Efficacy and safety of motor cortex stimulation for chronic neuropathic pain: critical review of the literature. J Neurosurg 2009;110:251–6.

18. Huygen FJPM, Baranidharan G, Simpson K, Patel NK, Love-Jones S, Green AL, Fitzgerald JJ, Wahlstedt A, Gatzinsky K, Breel J, Zuidema X, Wille F. An upper limb neuropathic pain cohort treated with stimulation of dorsal root ganglia (DRG): pooled data from four prospective European studies. Abstract. Las Vegas: 18th Annual Meeting of the North American Neuromodulation Society, December 11–14, 2014.

19. Keifer OP Jr, Riley JP, Boulis NM. Deep brain stimulation for chronic pain: intracranial targets, clinical outcomes, and trial design considerations. Neuro-surg Clin N Am 2014;25:671–92.

20. Kemler MA, Barendse GA, van Kleef M. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. New Engl J Med 2000;343:618–24.

21. Kemler MA, de Vet HC, Barendse GA. Effect of spinal cord stimulation for chronic complex regional pain syndrome type I: five-year final follow-up of patients in a randomized controlled trial. J Neurosurg 2008;108:292–8.

22. Kemler MA, De Vet HCW, Barendse GAM, Van Den Wildenberg FAJM, Van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized con-trolled trial. Ann Neurol 2004;55:13–8.

23. Kemler MA, De Vet HCW, Barendse GAM, Van Den Wildenberg FAJM, Van Kleef M. Spinal cord stimulation for chronic reflex sympathetic dystro-phy: five-year follow-up. New Engl J Med 2006;354:2394–6.

24. Kloimstein H, Likar R, Kern M, Neuhold J, Cada M, Loinig N, Ilias W, Freundl B, Binder H, Wolf A, Dorn C, Mozes-Balla EM, Stein R, Lappe I, Sator-Katzenschlager S. Peripheral nerve field stimulation (PNFS) in chronic low back pain: a prospective multicenter study. Neuromodulation 2014;17:180–7.

25. Kramer J, Liem L, Russo M, Smet I, Van Buyten JP, Huygen F. Lack of body positional effects on paresthesias when stimulating the dorsal root ganglion (DRG) in the treatment of chronic pain. Neuromodulation 2015;18:50–7.

26. Krames ES. The role of the dorsal root ganglion in the development of neu-ropathic pain. Pain Med 2014;15:1669–85.

27. Kumar K, Taylor RS, Jacques L. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 2007;132:179–88.

28. Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipović SR, Hummel FC, Jääskeläinen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schönfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014;125:2150–206.

29. Liem L, Russo M, Huygen FJPM, Van Buyten JP, Smet I, Verrills P, Cousins M, Brooker C, Levy R, Deer T, Kramer J. A multicenter, prospective trial to as-sess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain. Neuromodulation 2013;16:471–82.

30. Liem L, Russo M, Huygen FJPM, Van Buyten JP, Smet I, Verrills P, Cousins M, Brooker C, Levy R, Deer T, Kramer J. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuro-pathic pain. Neuromodulation 2015;18:41–9.

31. Manca A, Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, Taylor RJ, Goeree R, Sculpher MJ. Quality of life, resource consumption and costs of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial). Eur J Pain 2008;12:1047–58.

32. Moore NZ, Lempka SF, Machado A. Central neuromodulation for refrac-tory pain. Neurosurg Clin N Am 2014;25:77–83.

33. North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a randomized, controlled trial. Neurosurgery 2005;56:98–107.

34. North RB, Kumar K, Wallace MS, Henderson JM, Shipley J, Hernandez J, Mekel-Bobrov N, Jaax KN. Spinal cord stimulation versus re-operation in patients with failed back surgery syndrome: an international multicenter ran-domized controlled trial (EVIDENCE study). Neuromodulation 2011;14:330–6.

35. O’Connell NE, Wand BM, Marston L. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev 2014;4:CD008208.

36. Petersen E, Slavin K. Peripheral nerve/field stimulation for chronic pain. Neurosurg Clin N Am 2014;25:789–97.

37. Silberstein SD, Dodick DW, Saper J, Huh B, Slavin KV, Sharan A, Reed K, Narouze S, Mogilner A, Goldstein J, Trentman T, Vaisman J, Ordia J, Weber P, Deer T, Levy R, Diaz RL, Washburn SN, Mekhail N. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 2012;32:1165–79.

38. Simpson EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation. Health Technol Assess 2009;13: iii, ix–x, 1–154.

39. Slangen R, Schaper NC, Faber CG, Joosten EA, Dirksen CD, van Dongen RT, Kessels AG, Van Kleef M. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: a prospective two-center randomized con-trolled trial. Diabetes Care 2014;37:3016–24.

40. Slotty PJ, Eisner W, Honey CR, Wille C, Vesper J. Long-term follow-up of motor cortex stimulation for neuropathic pain in 23 patients. Stereotact Funct Neurosurg 2015;93:199–205.

41. Sukul V, Slavin K. Deep brain and motor cortex stimulation. Curr Pain Headache Rep 2014;18:1–5.

42. Tiede J, Brown L, Gekht G, Vallejo R, Yearwood T, Morgan D. Novel spinal cord stimulation parameters in patients with predominant back pain. Neuro-modulation 2013;16:370–5.

43. Torrance N, Lawson KD, Afolabi E, Bennett MI, Serpell MG, Dunn KM, Smith BH. Estimating the burden of disease in chronic pain with and without neuropathic characteristics: does the choice between the EQ-5D and SF-6D matter? Pain 2014;155:1996–2004.

44. Tsubokawa T, Katayama Y, Yamamoto T. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl Wien 1991;52:137–9.

45. Van Buyten JP, Al Kaisy A, Smet I, Palmisani S, Smith T. High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study. Neuromodulation 2013;16:59–66.

46. Van Buyten JP, Smet I, Liem L, Russo M, Huygen F. Stimulation of dorsal root ganglia for the management of complex regional pain syndrome: a pro-spective case series. Pain Pract 2015;15:208–16.

47. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014;155:654–62.

48. Wall PD, Sweet WH. Temporary abolition of pain in man. Science 1967;155:108–9.

49. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999;2:217–21.

50. Young NA, Sharma M. Transcranial magnetic stimulation for chronic pain. Neurosurg Clin N Am 2014;25:819–32.