Neurostimulation for Neuropathic Pain: Outcomes and New Paradigms

Neurostimulation for Neuropathic Pain: Outcomes and New Paradigms

®
XXI5••NO
1 • JUNE 2013
VOL XXIIIVOL
• NO
SEPTEMBER
2015
Neurostimulation forVol.ÊXXI,ÊIssueÊ1Ê
Neuropathic Pain:
Editorial Board and New Paradigms
Outcomes
N
Editor-in-Chief
europathic pain afflicts
JaneÊC.ÊBallantyne,ÊMD,ÊFRCA
millions of people globAnesthesiology,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
JuneÊ2013
PsychosocialÊAspectsÊofÊChronicÊPelvicÊPain
alternative therapeutic strategies for
recommendation based on a systematic
review and meta-analysis of published
patients with neuropathic pain.
and unpublished clinical trials.15 Data
Pain is unwanted, is unfortunately common,
and remains
for survival (i.e.,
Spinal
Cordessential
Stimulation
evading danger) and facilitating medical diagnoses. This complex amalgamation of
management of patients with chronic
Spinal
cord
(SCS)
as is
a a motisensation, emotions, and thoughts manifests
itself
as stimulation
pain behavior.
Pain
neuropathic
painfor
is physician
challenging,
with
1therapy for chronic pain was introand for emergency department visits and is
vating factor
consultations
from these studies suggest that the
more than 50% of patients experiencing
duced nearly half a century ago by
general population have pain with neu-
only partial or no relief of their pain. In
Norman Shealy and colleagues. Recent
ropathic characteristics.47 Neuropathic
addition, the adverse effects associated
advances in percutaneous implantation
pain can result from various etiologies,
with the drugs used to manage the pain
techniques and devices, technological
such as traumatic or surgical injuries to
may limit their clinical utility, particu-
advances in stimulation electrodes, in-
peripheral nerves, infectious diseases
larly in the elderly population. Hence,
novations in implantable pulse gen-
(e.g., herpes zoster, HIV, or leprosy),
erators, and the introduction of novel
metabolic disorders, cancer and its
stimulation parameters have resulted in
treatment, and injuries or diseases that
a surge in the use of implantable thera-
affect the central nervous system (e.g.,
pies. The relative safety and reversibil-
stroke or spinal cord injury). Nearly a
ity of this treatment modality, as well as
fourth of people with chronic diabetes
its cost-effectiveness over the long term,
have neuropathic pain—a worldwide
have made it an attractive strategy for
estimate of nearly 50 million indi-
managing patients with refractory,
viduals. Moreover, neuropathic pain is
experts are increasingly considering
chronic neuropathic pain. Although
reported to be more severe than non-
interventional therapies such as nerve
SCS has been used to treat a variety of
neuropathic pain and can dramatically
blocks and neuromodulatory strategies
neuropathic pain states, controlled trials
affect health-related quality of life.
for patients with refractory neuropathic
have shown the best evidence for long-
pain and those who are intolerant to
term efficacy in patients with failed back
mendations for pharmacological
systemic drugs. On the basis of the
surgery syndrome (FBSS) and complex
treatments have been published,
available evidence from clinical trials,
regional pain syndrome (CRPS) type I,
including a recently updated NeuPSIG
NeuPSIG published recommendations in
and more recently in diabetic neuro-
2013 regarding the use of interventional
pathic pain. Based on the GRADE cri-
therapies for neuropathic pain. Sev-
teria, a NeuPSIG consensus group rated
eral more recent studies have provided
the quality of evidence from clinical
additional evidence for the role of
trials as moderate, and gave it a “weak”
neurostimulation therapies in the man-
recommendation for use in FBSS with
agement of neuropathic pain. This
radiculopathy and CRPS.14 Although the
issue of Pain: Clinical Updates reviews
same report considered the evidence for
the latest evidence for emerging neuro-
the efficacy of SCS in diabetic neuro-
stimulation therapies that may provide
pathic pain to be low and labeled its
43
Several evidence-based recom-
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
14
13
1
recommendation as “inconclusive,” more
and the number of positive versus
recent controlled trials provide addi-
negative electrodes used. The amplitude
tional evidence for its efficacy.
is the strength of the stimulation pulse.
Stimulation Paradigms
Measured in volts or milliamps, it is the
primary control over the intensity of
Conventional SCS that is associated with
the sensation. Higher amplitudes will
a paresthesia uses a monophasic, square-
ultimately result in painful stimula-
wave pulse at a frequency in the 40–80-
tions. The highest amplitude that can be
Hz range. In an attempt to improve suc-
achieved with current devices is 15 V.
cess and avoid some of the undesirable
The pulse width is the amount of time
side effects of SCS, some physicians are
the stimulation pulse lasts and is mea-
using new stimulation parameters, such
sured in microseconds. Higher (wider)
as burst and high-frequency SCS (Fig. 1).
settings will cause the stimulation field
Recent studies examining the long-term
to “stay on” longer and depolarize both
effectiveness of these strategies provide
large- and small-diameter fibers. Lower
encouraging observations that should be
pulse width will narrow the stimula-
confirmed by additional controlled trials.
tion, resulting in mostly large-fiber
Traditional SCS
depolarization. Typical clinically used
pulse widths range from 175 to 600 µs
Whereas burst and high-frequency
but can go as high as 1000 µs. Frequen-
stimulation use fixed wave parameters,
cy is the number of stimulation pulses
traditional SCS adjusts the different pa-
delivered per second. The frequency of
rameters to achieve fiber depolarization
traditional SCS can be as high as 1200
and paresthesias that overlap the pain-
Hz. Increasing the frequency boosts the
ful area. Parameters that can be adjust-
number of action potentials generated
ed include electrode polarity, amplitude,
by the nerve. Changes in frequency
pulse width, and frequency. Electrode
produce a change in sensation from
polarity controls the shape and density
pulsing (low) to fluttering (high). Higher
of the electrical field, as determined by
frequencies dramatically affect battery
the distance between the electrodes
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 advantage of this stimulus paradigm is
that it does not cause paresthesia in
the painful region. In a randomized
controlled trial (RCT), burst stimulation 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.
2
PAIN: CLINICAL UPDATES • SEPTEMBER 2015
paresthesia mapping is not
necessary, thus shortening 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 patients with primarily lowback pain. Seventy-two
subjects had a successful
trial. Long-term follow-up
to 12 months showed a significant reduction in both
back and leg pain. The
study also reported significant improvements in the
average Oswestry Disability Index score and in
sleep disturbance, as well
as high patient satisfaction.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
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) Quality 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
provides both traditional
and high-frequency SCS
(the ACCELERATE Trial).
do not respond to tonic stimulation
alternating-current sinusoidal
Complex Regional Pain Syndrome
and improve pain reduction in those
waveform applied to a nerve results
CRPS is a well-established indication for
who do. Additional RCTs are needed
in reversible block of activity. This
SCS, for which it is approved by the U.S.
to confirm these observations
block occurs in three phases: an onset
Food and Drug Administration (FDA).
response, a period of asynchronous
The primary evidence for effective-
firing, and a steady state of complete
ness of SCS in CRPS patients is based
High-frequency stimulation uses fre-
or partial block. This technology is
on a prospective, randomized trial of
quencies up to 10 kHz. Although the
currently available in Europe and
54 patients followed for up to 5 years.
currently available device is capable
Australia and recently received ap-
Kemler and coworkers20 randomized
of amplitudes up to 15V and a pulse
proval in the United States. Because of
CRPS type I patients in a 2:1 ratio to two
width up to 1000 ms, newer devices
the high frequencies used, the device
groups: SCS with physical therapy or
reach 10 KHz with amplitudes of 1
requires a rechargeable battery to
physical therapy alone. Two-thirds of
to 5 mA and very low pulse width,
support the high power consumption.
the 24 patients in the SCS group were
resulting in paresthesia-free stimula-
It is used primarily to treat back pain
implanted with devices after a success-
tion. The exact mechanism of pain
but has some effect on lower-extremi-
ful trial stimulation. Pain was reduced
relief is unclear, but preclinical studies
ty pain. Leads are placed anatomically
by 2.4 cm on a 10-cm visual analogue
have shown that a high-frequency,
over T9 in the midline; intraoperative
scale (VAS) in the SCS group, whereas
8
High-Frequency Stimulation
PAIN: CLINICAL UPDATES • SEPTEMBER 2013
1
3
it increased by 0.2 cm in the physical
in pain. Among 45 patients available
invasive treatment options, includ-
therapy group. Moreover, 39% of SCS
for evaluation approximately 3 years
ing consideration of a trial of epidural
patients, compared to 6% of control
postoperatively, the authors reported
steroid injections.
patients, rated themselves as “much
a successful outcome in 47% of SCS
improved.” The observed beneficial
patients versus 11.5% of the reoperation
48 patients, burst stimulation led to a
effects in the SCS group persisted at 2
patients. The rate of crossover to alter-
significant additional pain reduction
years,22 but subsequent evaluations at
native treatment was also significantly
of approximately 28% in patients with
3–5-year follow-ups failed to demon-
lower in the SCS patients (~20%) than
FBSS, compared to that in patients
strate differences in outcome between
in the reoperation patients (>50%).
who received conventional tonic
23
the groups.
Despite a 42% reopera-
In the second, larger RCT, 100
In a recent observational study of
stimulation.10
tion rate in the SCS patients during the
FBSS patients with more severe leg
5-year study, 95% of the patients who
pain than back pain were randomized
Painful Diabetic Neuropathy
received SCS indicated that they would
to conventional medical management
Earlier small, prospective observational
repeat the procedure. Other retrospec-
(CMM) alone or CMM with SCS. The
trials evaluating the effects of SCS on
tive and prospective case series also
primary outcome measure was the re-
pain in patients with refractory painful
have reported reduced pain, improved
sponder rate (the proportion of patients
diabetic neuropathy (PDN) reported
function, and reduced medication use
obtaining at least 50% relief of leg pain)
substantial benefits, although the
after SCS in CRPS patients. An indepen-
at 6 months, after which patients were
complication rate was 33% in one of the
dent systematic review of the studies
allowed to cross over. In the 88 patients
trials.7,12 Two RCTs of SCS in patients
concluded that SCS showed evidence for
available for analysis, SCS was success-
with PDN reported in 2014 provide ad-
efficacy relative to conventional medical
ful in 48% and 34% at 6 and 12 months,
ditional evidence for the effectiveness
management in patients with CRPS type
respectively, in contrast to 9% and 7%
of SCS in the management of PDN. In a
I.38 Both NeuPSIG and the European
in the CMM group. More than 50% of
multicenter randomized trial, 36 PDN
Federation of Neurological Societies
subjects originally assigned to CMM
patients with severe lower-limb pain
(EFNS) gave a weak recommendation
crossed over to receive SCS, whereas
refractory to conventional therapy
for use of SCS in CRPS type I, on the
only 18% of SCS patients crossed over
were randomized to receive either SCS
basis of the moderate evidence.6,14
to CMM. Although the total health care
in combination with the best medical
cost in the SCS group was significantly
treatment (SCS group, n = 22) or medi-
higher, subjects in the SCS group expe-
cal treatment alone (BMT group, n =
Two published RCTs, along with several
rienced significantly improved quality
14).39 Treatment success, determined
long-term outcome case series, support
of life and functional capacity, as well
at 6 months, was defined as ≥50% pain
the use of SCS for FBSS. Most studies
as greater treatment satisfaction than
relief or “(very) much improved” for
evaluated the effects of SCS in patients
those in the CMM group.31 Device-
pain and sleep on the Patient Global
who had treatment-refractory FBSS
related reoperation is a concern, as 31%
Impression of Change scale.
with prominent radicular symptoms. In
of the SCS patients available for follow-
the first RCT, North et al. studied 50
up at 2 years had required surgical
in 59% of patients in the SCS group
patients who had undergone previous
revision. Considering the strengths and
compared to 7% in the BMT group. SCS
spinal surgeries and were candidates
limitations of these trials, the authors
was not without risk in this population,
for reoperation to alleviate chronic pain
of a systematic review concluded that
as one SCS patient died of a subdural
that was more bothersome in their legs
SCS appears to be more effective than
hematoma. In a second, larger, multi-
than their back. Patients were random-
CMM and reoperation.38 Both NeuPSIG
center controlled trial, 60 PDN patients
ized to either treatment with SCS or
and the EFNS gave SCS a weak recom-
were similarly randomized in a 2:1 ratio
reoperation, but they were allowed to
mendation for FBSS.6,14 Because of the
to receive best conventional medical
cross over to the other treatment if dis-
invasiveness of the procedure, the risk
practice with (SCS group) or without
satisfied with the results of their first
of complications, and the relatively
(control group) additional SCS therapy.11
treatment. The criterion for “success”
low response rate to SCS, the NeuPSIG
After 6 months of treatment, average
was patient satisfaction with treat-
recommendation was to reserve SCS
pain scores decreased significantly
ment and a 50% or greater reduction
for patients who do not respond to less
from 73 to 31 (0–100 VAS) in the SCS
21
Failed Back Surgery Syndrome
33
4
27
Treatment success was observed
PAIN: CLINICAL UPDATES • SEPTEMBER 2015
group, but remained unchanged at 67
technique.48,49 PNS has been used for
in the control group (Fig. 2). Improve-
a variety of chronic neuropathic pain
ments in quality of life measures were
states, such as postsurgical neuralgias,
also observed. In a recent observational
post-traumatic neuralgia, occipital
study that compared conventional
neuralgia, and postherpetic neuralgia
tonic stimulation with burst stimula-
(for review see Petersen and Slavin ).
tion, the latter led to a significant ad-
PNS has also been used to alleviate a
ditional 44% pain reduction on average
variety of headaches, including chronic
in patients with PDN.10
daily headaches, cluster headaches, and
Other Neuropathic Pain States
Editor-in-Chief
36
tion stump and phantom pains, posther-
occipital nerve PNS for migraine failed
petic neuralgia, spinal cord injury, and
to meet its primary endpoint (difference
other traumatic peripheral neuralgias.
in responders, defined as patients who
The evidence for effectiveness of SCS in
achieved a ≥50% reduction in mean dai-
these pain states has not been carefully
ly VAS scores).37 However, the authors
evaluated in controlled trials and is
did find significant reductions in pain,
based primarily on observational studies
headache days, and migraine-related
in small groups of subjects.
disability. Peripheral nerve field stimulation in the region of maximal pain
has also been used alone or in combina-
The success of SCS for neuropathic pain
tion with SCS, particularly for chronic
may depend on appropriate patient
axial low back pain.2,24 Although the
selection. Psychological traits may play
devices used for PNS are “off-label” in
an important role in modeling individ-
the United States, they are approved in
ual differences in the pain experience.
Europe for the treatment of intractable
Hence, psychological screening might
migraine and chronic low back pain.
be useful in helping to predict which
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 psychological and sensory profiles can reduce
the failure rate of SCS.
Peripheral Nerve/Field
Stimulation
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 effectiveness with time. Recently, the dorsal
root ganglion (DRG) has emerged as
a potential target for treating chronic
neuropathic pain 26. Experts hypothesize that, relative to traditional SCS,
stimulation of sensory neurons in the
DRG may result in more precise and
Peripheral nerve stimulation (PNS),
selective stimulation, thereby reduc-
first described nearly 50 years ago, has
ing unwanted side effects observed
recently become more attractive after
with traditional SCS.25 Some authors
the development of a percutaneous
postulate that DRG stimulation may be
PAIN: CLINICAL UPDATES • SEPTEMBER 2013
Pain Medicine, Palliative Medicine
Australia
Internal Medicine, Physiology
Italy
ized, double-blind, controlled trial of
that quantitative sensory testing may
Advisory Board
Michael J. Cousins, MD, DSC
Maria Adele Giamberardino, MD
uncontrolled case series. A random-
In addition, preliminary studies suggest
Anesthesiology, Pain Medicine
USA
ies reporting benefits of PNS have been
pathic pain states, such as post-amputa-
patients are likely to benefit from SCS.4
Jane C. Ballantyne, MD, FRCA
migraine, and to treat CRPS. Most stud-
SCS is used to treat several other neuro-
Predictors of Success
Editorial Board
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 findings, 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 assumed 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 contained 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:
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for the Study of Pain
1510 H Street NW, Suite 600,
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Tel: +1-202-524-5300
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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 multicenter, prospective, observational cohort
study, 32 of 51 subjects with chronic neuropathic 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.
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-
the North American Neuromodulation
tion in this population.
46
Noninvasive brain stimulation
techniques include repetitive tran-
Society also suggest promising benefits of
scranial magnetic stimulation (rTMS),
transcranial direct current stimula-
investigation. Huygen et al. reported
Motor Cortex and
Noninvasive Brain
Stimulation
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
DRG stimulation in mixed neuropathic
pain states that are worthy of further
18
Recently, 152 patients were enrolled
tion (tDCS), cranial electrotherapy
stimulation (CES), and reduced imped-
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
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
41
PAIN: CLINICAL UPDATES • SEPTEMBER 2015
its role as a therapeutic alternative (see
stimulation parameters, and the dura-
refractory neuropathic pain syndromes.
tion of stimulation. Reviewers postulate
50
that high-frequency (>5 Hz) stimulation
concluded that “there is a sufficient
leads to increased cortical excitability
body of evidence to accept with level A
Conclusions
and a reduction in cortical inhibition,
(definite efficacy) the analgesic effect of
The clinical literature now spans more
whereas low-frequency stimulation
high-frequency (HF) rTMS of the pri-
than three decades on the clinical
(≤1 Hz) causes a transient reduction in
mary motor cortex (M1) contralateral to
use of spinal cord stimulation to treat
cortical excitability without affecting
the pain.”28 Relative contraindications of
chronic neuropathic pain. Although
cortical inhibition.16 Although several
TMS include a history of epilepsy and
the evidence is “weak” on the efficacy
reports of uncontrolled trials suggest
the presence of aneurysm clips, deep
of this important therapy, this does not
that rTMS of the motor cortex (M1)
brain electrodes, and cochlear implants.
imply that it is not an effective therapy.
A recent evidence-based guideline
has beneficial effects in various central
review by Keifer et al.19 for details).
The “weak” evidence is not the result of
and peripheral neuropathic pain states,
Deep Brain Stimulation
results of controlled trials have been
Deep brain stimulation (DBS) is an
difficulties in successfully conducting
mixed. A recently updated Cochrane
accepted treatment for disorders like
controlled clinical trials with interven-
review35 included 56 trials (1710 ran-
Parkinson’s disease that are associ-
tional therapies.34 This problem stresses
domized subjects): 30 studies of rTMS,
ated with motor signs such as rigidity,
the need for alternative methods such
11 of CES, 14 of tDCS, and one study
bradykinesis, and tremor. The use of
as large registries to study the indi-
of RINCE. Several studies included a
chronic intracranial stimulation for
cations and clinical benefits of this
mixture of central, peripheral, and fa-
pain, however, remains controversial.
important therapy. Nonetheless, more
cial neuropathic pain states of various
Various DBS sites, including the inter-
recent, well-conducted studies support
etiologies. The authors concluded that
nal capsule, various nuclei in the sen-
both the efficacy and cost-effectiveness
single doses of high-frequency rTMS of
sory thalamus, the periaqueductal and
of this therapy in several neuropathic
the motor cortex may have small short-
periventricular gray, the motor cortex,
pain syndromes.
term effects on chronic pain (12%; 95% CI,
septum, nucleus accumbens, posterior
8–15%). In addition, multiple-dose studies
hypothalamus, and anterior cingulate
field of stimulation over the past three
failed to consistently demonstrate effec-
cortex, have been examined as poten-
decades, improvements in SCS technol-
tiveness, and low-frequency rTMS, rTMS
tial brain targets for pain control. The
ogy as well as new stimulation thera-
applied to the prefrontal cortex, CES, and
effectiveness of DBS has been the sub-
pies are emerging that should prove to
tDCS were ineffective in the treatment of
ject of case series in diverse etiologies
be an important addition to our stimu-
chronic pain. The primary advantage of
of chronic pain, but results have been
lation armamentarium. These new
these techniques is their excellent safety
inconsistent. Two multicenter trials
therapies are not likely to replace SCS,
profile, but the evidence for efficacy is in-
of DBS for chronic pain conducted in
but rather will supplement it or treat
conclusive and the magnitude of benefi-
the 1990s failed to demonstrate long-
patients not responsive to traditional
cial effects failed to meet the threshold of
term beneficial effects.5 Thus, current
SCS. By expanding the horizon of stim-
minimal clinical significance (≥15%) in the
evidence is inconclusive for determin-
ulation techniques, we will continue to
systematic review. Some have suggested
ing the role of DBS in the treatment of
successfully treat an increasing propor-
that rTMS can be used as a complemen-
neuropathic pain. Ongoing, better-con-
tion of neuropathic pain patients who
tary therapy in patients with chronic
trolled trials may shed more light on
currently have limited options.
References
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