®
VOL XXIIIVOL XXI5••NO
Neurostimulation forVol.ÊXXI,ÊIssueÊ1Ê
Neuropathic Pain:
Outcomes
Editorial Board and New Paradigms
N
Editor-in-Chief
europathic pain afflicts
JaneÊC.ÊBallantyne,ÊMD,ÊFRCA
millions of people glob-
Anesthesiology,ÊPainÊMedicine
USA ally and presents a major
health
AdvisoryÊBoard and economic bur-
den.MichaelÊJ.ÊCousins,ÊMD,ÊDSC
Epidemiological studies carried out
withPainÊMedicine,ÊPalliativeÊMedicine
validated screening tools estimate
Australia
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
Srinivasa N. Raja, MD
Department of Anesthesiology
and Critical Care Medicine
Johns Hopkins University
Baltimore, Md., USA
Email: sraja2@jhmi.edu
Mark Wallace, MD
Department of Anesthesiology
University of California
San Diego, Calif., USA
Email: mswallace@ucsd.edu
PAIN: CLINICAL UPDATES • SEPTEMBER 2015
PsychosocialÊAspectsÊofÊChronicÊPelvicÊPain
recommendation based on a systematic
alternative therapeutic strategies for
review and meta-analysis of published
and unpublished clinical trials.15 Data
Pain is unwanted, is unfortunately common,
from these studies suggest that the
evading danger) and facilitating medical diagnoses. This complex amalgamation of
management of patients with chronic
sensation, emotions, and thoughts manifests
neuropathic painfor
vating factor is physician
challenging, with
consultations 1therapy for chronic pain was intro-
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. Sev- 14
eral more recent studies have provided
additional evidence for the role of
neurostimulation therapies in the man-
agement of neuropathic pain. This13
issue of Pain: Clinical Updates reviews
the latest evidence for emerging neuro-
stimulation therapies that may provide
• NO 1 • JUNE 2013
SEPTEMBER 2015
JuneÊ2013
patients with neuropathic pain.
and remains
Spinal Cordessential for survival (i.e.,
Stimulation
Spinal cord
itself as stimulation (SCS)
pain behavior. as is
Pain a a moti-
-
and for emergency department visits and is
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
1
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
2 PAIN: CLINICAL UPDATES • SEPTEMBER 2015
and the number of positive versus Burst SCS
negative electrodes used. The amplitude
Burst stimulation consists of closely
is the strength of the stimulation pulse.
spaced, high-frequency stimuli
Measured in volts or milliamps, it is the
delivered to the spinal cord (Fig. 1).
primary control over the intensity of
The stimulus paradigm consists of a
the sensation. Higher amplitudes will
40-Hz burst mode of constant-current
ultimately result in painful stimula-
stimuli with 5 spikes at 500 Hz per
tions. The highest amplitude that can be
burst and pulse width and interspike
achieved with current devices is 15 V.
intervals of 1 ms. A possible advan-
The pulse width is the amount of time
tage of this stimulus paradigm is
the stimulation pulse lasts and is mea-
that it does not cause paresthesia in
sured in microseconds. Higher (wider)
the painful region. In a randomized
settings will cause the stimulation field
controlled trial (RCT), burst stimula-
to “stay on” longer and depolarize both
tion was able to improve back, limb,
large- and small-diameter fibers. Lower
and general pain by 51%, 53%, and
pulse width will narrow the stimula-
55%, respectively, compared to 30%,
tion, resulting in mostly large-fiber
52%, and 31% with tonic stimulation.
depolarization. Typical clinically used
Similar significant improvements in
pulse widths range from 175 to 600 µs
pain now, least pain, and worst pain
but can go as high as 1000 µs. Frequen-
were observed with burst stimulation.
cy is the number of stimulation pulses
The differences between tonic and
delivered per second. The frequency of
burst stimulation could be due to more
traditional SCS can be as high as 1200
selective modulation of the medial
Hz. Increasing the frequency boosts the
pain pathways by burst stimulation, as
number of action potentials generated
evidenced by activation of the dorsal
by the nerve. Changes in frequency
anterior cingulate cortex.9 More recent
produce a change in sensation from
retrospective analysis of patients who
pulsing (low) to fluttering (high). Higher
were switched from tonic to burst
frequencies dramatically affect battery
stimulation suggests that the latter
consumption.
can rescue a proportion of those who
Fig. 1. Spinal cord stimulation waveforms.

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
do not respond to tonic stimulation
and improve pain reduction in those
who do. Additional RCTs are needed
8
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,
PAIN: CLINICAL UPDATES • SEPTEMBER 2013
alternating-current sinusoidal
waveform applied to a nerve results
in reversible block of activity. This
1
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
3
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
23
the groups. 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
21
repeat the procedure. 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. studied 50
33
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
4 PAIN: CLINICAL UPDATES • SEPTEMBER 2015
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. The 27
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
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
PAIN: CLINICAL UPDATES • SEPTEMBER 2013
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 Slavin ).36
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, FRCA
Anesthesiology, Pain Medicine
USA
Advisory Board
Michael J. Cousins, MD, DSC
Pain Medicine, Palliative Medicine
Australia
Maria Adele Giamberardino, MD
Internal Medicine, Physiology
Italy
Robert N. Jamison, PhD
Psychology, Pain Assessment
USA
Patricia A. McGrath, PhD
Psychology, Pediatric Pain
Canada
M.R. Rajagopal, MD
Pain Medicine, Palliative Medicine
India
Maree T. Smith, PhD
Pharmacology
Australia
Claudia Sommer, MD
Neurology
Germany
Harriët M. Wittink, PhD, PT
Physical Therapy
The Netherlands
Publishing
Daniel 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 translate
this article, contact:
International Association
for the Study of Pain
1510 H Street NW, Suite 600,
Washington, D.C. 20005-1020, USA
Tel: +1-202-524-5300
Fax: +1-202-524-5301
Email: iaspdesk@iasp-pain.org
www.iasp-pain.org
5
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
Fig. 3. Lead placement for dorsal root ganglion stimulation.
results were observed in a group of
subjects with lower-extremity CRPS or CRPS. The study’s results, which will motor cortex stimulation during the
(8 of 11 trialed subjects received device include safety and efficacy endpoints first few months, the pain relief may
implants) who were followed for a year. 46
and responder rate analysis, may help to wane over longer periods of time.17,40
Several recent abstracts presented at determine the efficacy of DRG stimula- Noninvasive brain stimulation
the North American Neuromodulation tion in this population. techniques include repetitive tran-
Society also suggest promising benefits of scranial magnetic stimulation (rTMS),
DRG stimulation in mixed neuropathic Motor Cortex and transcranial direct current stimula-
pain states that are worthy of further Noninvasive Brain tion (tDCS), cranial electrotherapy
investigation. Huygen et al. reported
18 Stimulation stimulation (CES), and reduced imped-
pooled data from prospective studies in Motor cortex stimulation is based on ance noninvasive cortical stimula-
Europe of 19 patients with upper-limb an observation nearly 25 years ago tion (RINCE; for recent reviews, see
neuropathic pain of various etiologies by Tsubokawa et al.44 that stimulation O’Connell et al.35 and Young et al.50).
and showed mean reductions in pain of the precentral gyrus below motor In contrast to conventional electrical
of 54.6% and 58.6% at 3 and 6 months, threshold relieves pain in patients with stimulation that is likely to reach only
respectively, with concurrent improve- thalamic pain. A number of subsequent the most superficial layers of the cortex,
ments in quality of life. clinical observations have shown ef- the magnetic field created by rTMS
Recently, 152 patients were enrolled ficacy in trigeminal neuropathic pain passes through the scalp and cranium
in a prospective, randomized, multi- and deafferentation syndromes such as to excite or inhibit various cortical and
center, controlled trial (ACCURATE poststroke pain and pain resulting from subcortical neural networks. Similar
Trial) designed to evaluate the safety spinal cord injury or brachial plexus in- to other neuromodulation techniques,
and efficacy of a DRG stimulation device juries (for reviews see Sukul and Slavin 41 the effects of rTMS may depend on the
for treatment of chronic lower-limb and Moore et al.32). Although more than positioning of the coil and its orientation
pain caused by nerve injuries (causalgia) 50% of patients appear to respond to to the underlying brain structures, the

6 PAIN: CLINICAL UPDATES • SEPTEMBER 2015

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.  tive study on tonic versus burst spinal cord stimulation: amount of responders
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-
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 2013 7

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.
8 PAIN: CLINICAL UPDATES • SEPTEMBER 2015
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.