Download Clinical evidence for dorsal root ganglion stimulation in the treat

(Acta Anaesth. Belg., 2015, 66, 37-41)
Clinical evidence for dorsal root ganglion stimulation in the treatment of chronic neuropathic pain. A review
P. Forget (*, **, #), Th. Boyer (*, #), A. Steyaert (*, #), E. Masquelier (**, ***), R. Deumens (**)
and B. le Polain de Waroux (*, **)
Abstract : Treating chronic neuropathic pain remains a
challenge, despite the existing therapies. Recent years
have seen the emergence of promising new technologies,
such as the neurostimulation of the dorsal root ganglion
(DRG). In the present article, we review the clinical evidence for the efficacy and safety of DRG neurostimulation in the treatment of chronic pain. While the results
from a number of small observational studies are promising, it is not yet possible to conclude on the long-term
effectiveness and safety of DRG stimulation and it is too
early to recommend its widespread use outside of a research protocol. To improve the level of proof, larger
randomized controlled trials are needed. These should
include well-described populations, a sufficiently long
follow-up and a detailed description of concurrent treatments (pharmacologic and patient integration in a multidisciplinary approach).
Key words : Dorsal root ganglion ; chronic pain ; neuro­
pathic ; neurostimulation ; stimulation ; neuromodulation.
Introduction
Treating chronic neuropathic pain remains difficult, despite the existing therapeutics (1). Spinal
cord stimulation (SCS) is integrated in chronic pain
algorithms and is one of the options for refractory
neuropathic pain, when conservative treatment is
insufficient (2). Levels of efficacy are variable, between 40 and 70% depending on the studies (3, 4).
In the last few years, new technologies have emerged
that could lead to better results, for example burst
stimulation and high frequency stimulation (4). Alternatively, neurostimulation of other anatomical
sites has been proposed, most recently of the dorsal
root ganglion (DRG) (5). Various arguments have
been made for its superiority over spinal cord stimulation, both fundamental (6, 7, 8) (DRG involvement in the pathophysiology of chronic pain) and
clinical (9) (ease of implementation of the electrode,
better targeted efficiency expected).
Indeed, several features make the DRG an appealing site for developing new analgesic approach-
es. The dorsal root ganglion (DRG) resides at each
segmental level of the spinal column and contains
sensory neuron somata for all sensory modalities
and fiber types (10). Elevated excitability of sensory neurons in the DRG contributes to the development of chronic pain that follows peripheral nerve
injury. Stimulation at this site engages the spinal
and supraspinal mechanisms — as occurs in SCS
— and provides an opportunity for directly modulating function of Ad- and C-type fibers that convey
pain. Finally, sensory neuron stimulation has been
shown to diminish neuronal excitability. Based on
these key features, we can assume that the stimulation of the DRG may reduce chronic pain pathogenesis and block the conduction of pain from more
distal pain-generating sites (11).
In order to evaluate the level of proof for the
efficacy and safety of this technique (DRG stimulation to treat chronic neuropathic pain patients), we
analysed the peer-reviewed scientific literature and
report the results.
Methods
In accordance with the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines, acquisition of data on the
29th October 2014 was based on the consultation of
the PubMed database and its search by one list of
Patrice Forget ; Thomas Boyer ; Arnaud Steyaert ; Etienne
Masquelier ; Ronald Deumens ; Bernard le Polain de
Waroux.
(*) Anaesthesiology Department, Cliniques Universitaires
Saint-Luc, (**) Institute of Neuroscience, Université
catholique de Louvain, (***) Physical Medicine, Cliniques
Universitaires Saint-Luc, Brussels, Belgium.
Correspondence address : Thomas Boyer, Anaesthesiology
Department, Cliniques universitaires Saint-Luc, 1200 Brussels, Belgium. Tel. : +3227641821. Fax : +3227643699.
E-mail : [email protected]
# The first three authors equally contributed to the manuscript.
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et al.
Fig. 1. — Flow diagram
keywords for all available articles in English and
French, without defined period.
The keywords used in the research were :
“dorsal root” AND (“neuromodulation” OR “neurostimulation”) (n = 47). The abstract of the selected
articles were then read by the authors of this review
to exclude case reports and articles not dealing with
clinical study on DRG stimulation for chronic pain
treatment. Twenty-one articles on basic research
(not involving patients) were excluded. Three studies focusing on pulsed radiofrequency as well as
five on spinal cord stimulation, three on peripheral
nerve stimulation and six about neurosurgery were
excluded. Finally, three articles based on case reports were excluded. In the end, six papers were
identified and included for analysis : five prospective (12, 13, 14, 15, 16) and one retrospective (17)
(Fig. 1).
The qualitative and, when possible quantitative, criteria analysed for each study were : funding
sources and their potential influence, participants
(patients and pain characteristics), intervention
(modalities of electrodes implantation, test period,
integration of stimulation in documented multi­
disciplinary approach), comparisons (to baseline,
presence/absence of a control group), and outcomes
(pain scores, medications, follow-up, complications).
Results
In 2013, Deer et al. reported data from a pilot
study for the ACCURATE study (NCT01923285),
sponsored by Spinal Modulation, Inc., Menlo Park,
CA, USA and whose results are not to be expected
before 2018 (12). Four centres participated and
­included 10 patients in one arm (5 men/5 women,
average age 46 ± 5 years). Six had radicular pain
and four other types of neuropathic pain (one diabetic, one post-herpetic, and two non-specified origin). These pains were refractory to a well-led treatment and stable for at least 30 days. The electrodes
for DRG stimulation were implanted percutaneaously, similarly to posterior cord stimulation.
The study did not include a control group. The primary endpoints were the reduction of mean pain
score (visual analogic scale, VAS) and the proportion of patients with more than 30% reduction of
pain. Patients were followed-up for three to seven
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days. The authors reported an average of 70% reduction in pain scores and 80% (8/10) of patients
with more than 30% pain reduction. Fourteen complications were reported, including transient increase of pain associated with probes (n = 3),
migration of a probe (n = 1), antibiotic reaction
­
(n = 1) and inactivation of the stimulation due to
changes of the system impedance (n = 7). Two
complications were not further described. Limitations of this study include its very small sample
size, open-label design, lack of detailed description
of the patients (e.g. concurrent medications) and
very short follow-up period.
The same year, Liem et al. reported the data of
two independent, prospective, open label, singlearm observational studies sponsored by Spinal
Modulation, Inc., one conducted in Europe (3 sites)
and one in Australia (4 sites) (13). The identical inclusion, exclusion and judgment criteria for both
samples allowed the authors to regroup both studies
into one. Fifty-one patients were included, all suffering from neuropathic pain in the trunk, limbs or
sacral region resistant to other treatment modalities,
lasting a minimum of 6 months. Those 51 patients
were implanted with temporary electrodes connected to an external neurostimulator. Thirty-nine had a
positive test period (3 to 30 days, pain reduction
greater than 50% according to VAS). Out of those
39 patients considered for an internal stimulator,
32 patients were effectively implanted (2 showed
lack of compliance, 2 refused implantation and 3
were explanted for infection). Patients were followed up for six months. At two time points, stimulation was turned off for one week and these two
periods were used as a control group. The primary
end-point of this study was to evaluate the safety
(adverse event rate) and feasibility (paraesthesia
generation) of the DRG stimulation technique with
the Axium neurostimulator. A total of 70 complications were reported, 9 of which were deemed
severe : “3 infections affecting 3 patients, one
­
hygroma, one paraesthesias loss, one prolonged
­
hospitalization, one inflammation, one transient
cessation of stimulation and one ataxia”. The secondary objective was to assess efficacy, including
pain relief and improvement in quality of life, mood
and physical functioning. At six months follow-up,
the authors report more than 50% pain reduction for
over 50% patients as well as improvements on most
other secondary measures.
In a second paper, the same team described the
follow up of the same sample after 12 months (14).
Over this period, a total of 86 adverse events were
reported, approximately halve of which were
deemed related with the device. Among those, the
most severe were twelve temporary motor stimulations, seven infections and seven cerebrospinal fluid
leaks with associated headache. Four lead revisions
needed to be completed and there was also one lead
fracture. One implantable generator revision was
also performed and a total of seven patients had
their device explanted for various reasons (infections, lack of efficacy or lack of compliance with
study procedures). After twelve months, the authors
reported the same improvement on pain, mood and
quality of life as previously described after 6 months.
Limitations of this study include its relatively small
sample size, one-arm design without real control
group and lack of description of the patient population (e.g. duration of the pain syndrome, concurrent
medication…).
In a separate paper, Van Buyten et al. reported
on the specific use of DRG stimulation on the subgroup of patients suffering from Complex Regional
Pain Syndrome (CRPS) patients (15). CRPS diagnosis was based on standard (Budapest) criteria but
no details were provided on the stage of the disease.
Patients were part of the larger prospective study
previously described (14). Out of the eleven subjects trialled, eight reported over 50% pain relief
and were subsequently implanted with a permanent
neurostimulator. One patient was explanted after
one month due to insufficient pain relief. Twelve
months later, six patients still felt pain relief greater
than 50%. Average pain intensity and pain inference were significantly reduced, while mood and
quality of life were improved. Three patients also
reported neurovascular changes or improvement
mobility. Eleven adverse effects were reported, of
which three were deemed severe and three definitely related to the device. In the discussion, the authors compared these results with SCS stimulation.
While pain relief obtained was similar, advantages
of DRG stimulation included less lead migration, a
better ability to achieve pain-paraesthesia overlap
and a stability of the stimulation regardless of body
position. Limitations of this study include its very
small sample size, one-arm design and lack of
­details concerning the patients (e.g. stage of the
­disease or concurrent medication).
In a second substudy, Kramer et al. tried to
demonstrate the stability of the DRG stimulation
across body positions. At each time-point, all patients were asked to report paraesthesia intensity
both in supine and upright position, while stimulation programming was kept constant. Both paraesthesia intensity scores and location were similar between these two body positions and over time (16).
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Schu et al. retrospectively reviewed the data
from 29 patients suffering from neuropathic groin
pain from 11 European institutions (private, academic and teaching hospitals), whose condition was
not improved by usual treatments (17). Twenty-five
patients had an improvement in their pain symptoms after a test period with external stimulation
from 3 to 30 days and were implanted with an internal stimulator. Twenty-three patients were followed
up for a median of 26 weeks (0-68 weeks) and reported a 65 to 75% decrease in pain, with over 80%
of patients describing a reduction of their symptoms
by more than 50%. There was no follow-up data
available for one patient and one other patient had
his stimulator removed. A subgroup of patients
(n = 13) had a follow-up of 6 months or more, with
results similar to the entire series. In their conclusion the authors highlighted the accuracy and stability of DRG stimulation but possible complications
related to treatment were neither reported nor discussed. The retrospective nature of this study and
the lack of detailed information on the patient population are other limitations of this study.
Discussion
The six papers included in this review clearly
demonstrate the feasibility of DRG stimulation as a
treatment option for neuropathic pain. However,
they cannot demonstrate either its safety (the number of patients included is too small) or its long-term
efficacy (lack of control group, mostly short followup with a variable length limiting the analysis in
many cases to the qualitative level). It should be
noted that Spinal Modulation, Inc. sponsored all the
available studies, which could result in conflicts of
interest. However, it is the only company that currently is proposing a device for DRG stimulation.
To improve the level of proof, larger randomized controlled trials are needed. Of course, we
acknowledge that creating a placebo-controlled
­
neurostimulation study with a blinded control group
is very challenging, if not impossible. Moreover,
­realizing that chronic pain is difficult to evaluate,
we agree with those who suggest that the use of
­psychological and functional assessment and tools
such as laser-evoked potentials (LEPs) and quantitative sensory testing (QST) may be important, first
to understand symptoms and then to determine
which type of population may benefit the most from
treatments such as neuromodulation (18).
While further research is needed and only a
trial comparing the two stimulation sites could provide a definitive answer, existing studies neverthe-
et al.
less suggest some possible advantages of DRG
stimulation compared to SCS. First, it is well demonstrated that eliciting paraesthesia in certain areas
of the body (e.g. the groin or one extremities) is difficult with SCS and that this can be a cause of failure (19). The scope of this problem however, may
vary depending the team’s experience. While it is
not proven at this stage that DRG stimulation provides a definite advantage, it seems that achieving
pain-paraesthesia overlap is easier with DRG stimulation, as described by Van Buyten et al. and Shu et
al. (15, 17). A second proposed advantage of the
DRG stimulation is the consistency of effect, irrespective of the position of the patient, as highlighted
by the paper by Kramer et al. (16). With SCS, the
quality of the stimulation may vary depending on
the position of the subject, even though the precise
influence of this phenomenon on the analgesic effect has never been formally demonstrated. While
one could consider that this advantage results only
in improved patients’ confort rather than a superior
analgesic effect per se, the difficulty for the patient
to adapt to the variations in perceived stimulation
intensity can also be a cause of failure of SCS.
Thirdly, DRG stimulation requires lower current
amplitude than SCS to elicit paraesthesia, which in
turn could enhance battery life of the implanted
neurostimulator (16). Finally, lead migration rates
seem to be lower, which could limit the number of
surgeries for lead replacement (15). On the other
hand, there could be a risk of increased technical
difficulties and complications related to the multiplication of electrodes.
All these possible benefits suggest some specific indications for DRG stimulation. These could
include : localized pain after surgery (for example
orthopedic surgery or groin surgery), post-thora­
cotomy chronic pain, failed back surgery syndrome,
isolated radiculopathy requiring a very precise location of paraesthesia, highly mobile patients seeking
constant stimulation and cognitive impairments preventing the rapid adaptation of stimulation intensities in case of change in position.
In conclusion, based on the most recent literature, we consider DRG stimulation a promising
technique for the treatment of chronic neuropathic
pain. Current evidence however does not yet support its widespread use outside a research protocol
and larger trials are needed to improve the level of
proof. Study designs should ideally be randomized
controlled trials and include well-described populations, long enough follow-up and thorough description of concurrent treatments (pharmacologic and
patient integration in a multidisciplinary approach).
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