Journal of Neural Transmission

https://doi.org/10.1007/s00702-019-02092-y

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Neurostimulation methods in the treatment of chronic pain

X. Moisset1   · M. Lanteri‑Minet2,3 · D. Fontaine4

Received: 12 July 2019 / Accepted: 6 October 2019

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Abstract
The goal of this narrative review was to give an up-to-date overview of the peripheral and central neurostimulation methods
that can be used to treat chronic pain. Special focus has been given to three pain conditions: neuropathic pain, nociplastic
pain and primary headaches. Both non-invasive and invasive techniques are briefly presented together with their pain relief
potentials. For non-invasive stimulation techniques, data concerning transcutaneous electrical nerve stimulation (TENS),
transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), remote electrical neuro-
modulation (REN) and vagus nerve stimulation (VNS) are provided. Concerning invasive stimulation techniques, occipital
nerve stimulation (ONS), vagus nerve stimulation (VNS), epidural motor cortex stimulation (EMCS), spinal cord stimulation
(SCS) and deep brain stimulation (DBS) are presented. The action mode of all these techniques is only partly understood
but can be very different from one technique to the other. Patients’ selection is still a challenge. Recent consensus-based
guidelines for clinical practice are presented when available. The development of closed-loop devices could be of interest
in the future, although the clinical benefit over open loop is not proven yet.

Keywords  Chronic pain · Neuropathic pain · Primary headache · Magnetic stimulation · Neuromodulation

Introduction fibromyalgia, the main nociplastic pain type, nearly 2%

(Bouhassira et al. 2008; Fayaz et al. 2016; Heidari et al.
Chronic somatic pain affects around 20% of the general 2017). Headache disorders, and migraine in particular, are
population (Breivik et al. 2006). It can be subdivided into also important causes of disability worldwide (GBD 2016
nociceptive, neuropathic and nociplastic pain, the last hav- Headache Collaborators 2018). Migraine is present in at
ing recently been defined by the International Associa- least 15% of the adult population and around 1% of the
tion for the Study of Pain (IASP) as pain that arises from general population suffers from chronic daily headache
altered nociception despite no clear evidence of actual or (Lantéri-Minet et al. 2005; Buse et al. 2012; Smitherman
threatened tissue damage causing the activation of periph- et al. 2013). Several other pain types are less frequent
eral nociceptors or evidence for disease or lesion of the but particularly debilitating, for example, chronic cluster
somatosensory system causing the pain. Chronic neuro- headache. Many of these chronic pain patients have inad-
pathic pain concerns around 8% of the population and equate relief or disabling side effects using currently avail-
able pharmacological treatments. Thus, there is a need
for other therapeutic proposals and neurostimulation is
* X. Moisset one of these.
xavier.moisset@gmail.com The goal of this brief narrative review is to give an over-
1
Service de Neurologie, Université Clermont-Auvergne,
view on invasive and non-invasive neurostimulation tech-
INSERM, Neuro-Dol, CHU Clermont-Ferrand, niques used to allow pain relief in neuropathic pain, noci-
Clermont‑Ferrand, France plastic pain (mainly fibromyalgia) and headaches. Articles
2
Pain Department, CHU Nice, FHU InovPain Côte Azur known by the three authors were used without performing
University, Nice, France a systematic review.
3
Université Clermont-Auvergne, INSERM, Neuro-Dol,
Clermont‑Ferrand, France
4
Department of Neurosurgery, Université Côte Azur
University, CHU de Nice, FHU InovPain, Nice, France

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 X. Moisset et al.

Non‑invasive stimulations techniques Moreover, this non-invasive technique is well tolerated,

presents minor and transient side effects (mainly cutaneous
Neuropathic pain irritation) and has a limited cost, with devices available
for less than 250 euros. Some patients have benefit only
Transcutaneous electric nerve stimulation (TENS) during TENS use, whereas others describe a lasting post-
effect using a daily 30 min session.
TENS is thought to activate a complex neuronal network
leading to a reduction in pain. In practice, TENS is applied Transcranial direct current stimulation (tDCS)
at varying frequencies, intensities, and pulse durations of
stimulation (Sluka and Walsh 2003). Different modes can Transcranial direct current stimulation (tDCS) is a type of
be described. Conventional TENS corresponds to the use electrical stimulation delivered continuously (“direct cur-
of high frequency (100 Hz or more), low intensity and rent”) for 20–30 min at a low intensity (Moisset and Lefau-
a short pulse duration (50–80 µs). This combination of cheur 2018). Usually, two large electrodes are placed on the
parameters activates non-noxious afferent nerve fibers (Aβ scalp, one anode and one cathode. For pain treatment, the
fibers). The effect of such mode is traditionally attributed conventional bipolar montage comprises the anode over the
to the activation of these fibers thought to modulate Aδ primary motor cortex (M1) and the cathode over the con-
and C fiber-mediated nociceptive transmission in the tralateral supraorbital region. This produces a large current
spinal cord, compatible with the ‘gate control theory of flow in various brain structures, such as the prefrontal cortex,
pain’ (Melzack and Wall 1965). Such segmental inhibi- the cingulate cortex, the insula, and even deeper structures
tion starts quickly but do not last very long. There is now (thalamic and brainstem nuclei) (DaSilva et al. 2015). The
experimental evidence suggesting that descending pain- focality of the stimulation can be enhanced by other types of
modulating pathways are also involved in the analgesic montages presented as “high-definition” tDCS (HD–tDCS).
effects, explaining the post-effect that can be seen in some The clinical benefit of such HD montages needs to be further
patients. On the contrary, acupuncture-like TENS corre- investigated in pain syndromes.
sponds to the use of low frequency (1–4 Hz) and high The use of tDCS at the intensity of 12 mA is totally safe
intensity (enough to produce muscle contractions) and a for brain structures, the only risk in clinical practice being
long pulse duration (~ 200 µs). Acupuncture-like TENS producing skin burns because of inaccurate electrode–skin
stimulates mainly small nociceptive fibers (Aδ and C) but contact (Antal et al. 2017). In addition, the device is small
also small motor fibers. This second mode of TENS is and easily portable. Therefore, this technique is especially
believed to operate primarily via the release of endog- suitable to be applied at home by the patient for long-term
enous opioids. Thus, there is a relatively longer onset to pain treatment (Pérez-Borrego et al. 2014). The cheapest
analgesia, but the analgesia typically lasts longer with this devices cost less than 300 euros. For clinical and research
mode than with conventional TENS. The third mode that applications, CE-marked and well-designed systems cost
can be used corresponds to burst mode. Trains of pulses at around 3000 euros (Moisset and Lefaucheur 2018). The
100 Hz are applied 1–4 times per second, corresponding to contraindications to this technique are the presence of head
a mix between conventional and acupuncture-like modes. implants, tumor or hypertrophic skin scars below the elec-
A better analgesia can probably be obtained with higher trodes. The technique should be used with caution in case
intensities but the patients must feel a comfortable tingling of a history of seizures, cranial bone defect or cranial skin
(with high frequency) or tapping (with low frequency) that scars (Baptista et al. 2019).
should never be painful (Moran et al. 2011). TENS can be Contrarily to epidural motor cortex stimulation (EMCS)
proposed only when the size of the pain area is limited and and repetitive transcranial magnetic stimulation (rTMS) that
when cutaneous sensitivity still exists. It is contraindicated produce direct neuronal stimulation (i.e., action potentials),
in case of contact allergy to the electrodes or major skin the intensity of current induced into the brain by tDCS is
lesions at the place of electrodes. Electrodes should never too low and not sufficient to elicit action potentials in cor-
be placed over the eyes or on the anterior aspect of the tical axons (Nguyen et al. 2011; Nizard et al. 2012). The
neck over the carotid sinuses, as the baroreceptor could be aim of tDCS is to modulate the rest membrane potential of
directly stimulated and induce a drop in blood pressure. axons. Thus, a modification towards depolarization favors
TENS can also interfere with certain types of pacemakers axonal excitability, whereas hyperpolarization decreases
and a first trial with concomitant ECG should be proposed. it, depending on electrode polarity and axonal orientation
Many studies concerning TENS in chronic peripheral neu- (Lefaucheur 2012). The first beneficial effect of anodal
ropathic pain have been published. Although the overall tDCS over M1 for the treatment of central pain secondary
quality of the studies is low, there is a positive effect of to spinal cord injury was published more than 10 years ago
active TENS compared to sham (Gibson et  al. 2017). (Fregni et al. 2006). Since then, numerous studies showed

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Neurostimulation methods in the treatment of chronic pain

interesting perspectives for the use of tDCS to treat vari- probably be extrapolated to rTMS. The contraindications
ous pain syndromes (Lefaucheur 2016). However, the level are the presence of ferromagnetic material in the stimulation
of evidence of efficacy for anodal tDCS of the left M1 is area, especially cochlear implant or the existence of epilepsy.
limited in chronic neuropathic pain resulting in a level C Several types of coils can be used to apply rTMS (Deng
recommendation, restricted to lower limb pain secondary to et al. 2013), but almost all studies are performed with focal
spinal cord lesion (Lefaucheur et al. 2017) and level B for figure-of-eight coils (F8c), limiting the stimulated area to
peripheral neuropathic pain (Baptista et al. 2019). Only two a few square centimeters at a depth of less than 2 cm. This
studies have evaluated tDCS efficacy with anode over left focal stimulation makes the use of a neuronavigation sys-
DLPFC in neuropathic pain conditions, without sustained tem that is helpful in allowing comparable and reproduc-
benefit in those two cases (Kim et al. 2013; Ayache et al. ible stimulation targeting between sessions, especially for
2016). Thus, this technique is not recommended. non-motor cortical targets (Ahdab et al. 2010; Lefaucheur
The analgesic effect of other forms of low-intensity elec- 2010). Other types of coils have been proposed to stimu-
trical stimulation delivered transcranially, such as transcra- late deeper brain structures (Ciampi de Andrade et al. 2012;
nial alternating current stimulation (tACS) or transcranial Hodaj et al. 2018). A recent study has shown that targeting
random noise stimulation (tRNS), has not been proven in anterior cingulate cortex or the posterior superior insula was
neuropathic pain (Palm et al. 2016). Transcranial ACS and not effective in reducing central neuropathic pain (Galhar-
RNS use the same type of montages as tDCS, with two doni et al. 2019). Using Hesed coils (H-coils) also allows
electrodes placed on the scalp. While tDCS uses direct cur- deep stimulation but has only been tested in a very limited
rent (stable current intensity leading to membrane poten- number of studies concerning neuropathic pain (Onesti et al.
tial modification), tACS corresponds to alternative current 2013; Shimizu et al. 2017; Cervigni et al. 2018).
and tRNS to randomly varying current, within a predefined In practice, an rTMS session lasts about 15–30 min. When
range. Likewise, another modality of electrical stimulation, using a F8c, an anteroposterior or posteroanterior orientation
called cranial electrotherapy stimulation (CES) exists. CES provides optimal pain relief (André-Obadia et al. 2008). The
involves the application of a small amount of current through intensity of stimulation is adapted for each subject accord-
the head via ear clip electrodes but has not proven a ben- ing to its motor threshold. Stimulation is usually performed
efit for the treatment of chronic pain syndromes (O’Connell using 80 or 90% of this motor threshold. The stimulation
et al. 2018). pattern must be composed of trains of pulses delivered at
‘high frequencies” (between 5 and 20 Hz) spaced by pauses
Repetitive transcranial magnetic stimulation (rTMS) of several seconds. Train and inter-train durations, accord-
ing to the frequency of stimulation, must remain within the
Repetitive transcranial magnetic stimulation (rTMS), first safety limits, which have been proposed to reduce the risk of
described by Faraday in 1831 relies on electromagnetic seizures (Rossi et al. 2009). Reducing session duration via
induction. Concerning rTMS, a brief magnetic pulse is reducing inter-train intervals may lower the intensity of the
delivered by a coil placed on the scalp and passes through analgesic effects (Hodaj et al. 2015). New protocols using
the skull with minimal attenuation, leading to axonal depo- theta-burst stimulation could be of interest in pain treatment
larization within the superficial cortical layers (Kobayashi to reduce session duration (Moisset et al. 2015), as recently
and Pascual-Leone 2003; Lefaucheur et al. 2008; Lefaucheur proven for depression (Blumberger et al. 2018).
2009). The mechanisms at the origin of the analgesic effects For clinical routine, a neuronavigation system is not man-
of high-frequency rTMS of M1 are very similar to those datory to stimulate M1, but clearly helpful in the manage-
of EMCS, as shown by the late I-waves generated in both ment of long-term treatment (Pommier et al. 2016; Quesada
cases and the predictive value of rTMS in EMCS efficacy et al. 2018). For patients that do not respond to motor hot-
(Lefaucheur et al. 2011; André-Obadia et al. 2014). Such spot rTMS, we wonder if targeting somatotopic representa-
stimulation modulates neural activity in pain networks in tions of painful body parts can be helpful. To date, data
remote brain regions (Lefaucheur 2008; Nizard et al. 2012; are insufficient to be sure of the beneficial effect of such
Moisset et al. 2016). Several neurotransmitter systems have a strategy and it still needs to be validated in prospective
been implied, involving complex opioidergic, glutamater- studies (Lefaucheur et al. 2006b; Andre-Obadia et al. 2018).
gic, or GABAergic modulations (Lefaucheur et al. 2006a; The minimum required material costs around 30,000 euros.
de Andrade et al. 2011; Ciampi de Andrade et al. 2014). From now on, meta-analyses showed a rather benefi-
Indeed, using an opioid antagonist such as naloxone or a cial impact of high-frequency rTMS of M1 on neuropathic
glutamatergic antagonist such as ketamine before rTMS pain (Leung et al. 2009; Jin et al. 2015), although effect
significantly reduces analgesic effect of the stimulation. size seems limited (O’Connell et al. 2018). A single rTMS
As the mechanisms of action for rTMS are supposed to be session induces maximal pain relief after 2–3 days and can
very similar to that of EMCS, data obtained in EMCS can last up to 8 days (Lefaucheur et al. 2001). For therapeutic

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 X. Moisset et al.

purposes, a few studies showed the value of a maintenance recommendation for use in fibromyalgia has been proposed
protocol of high-frequency M1-rTMS sessions to manage (Baptista et al. 2019).
chronic neuropathic pain in clinical practice in the long Concerning the montage with anode over the left DLPFC,
term (Pommier et al. 2016; Quesada et al. 2018). Therefore, only two studies were conducted and without any benefit at
recommendations now exist for the use of high-frequency follow-up in both cases (Fregni et al. 2006; Valle et al. 2009)
rTMS of M1 to treat patients with chronic neuropathic pain Thus, this technique is not recommended according to the
syndrome (Lefaucheur et al. 2014; Cruccu et al. 2016; Bap- recent guidelines.
tista et al. 2019). Concerning other cortical targets, level B
recommendation against the use of high-frequency rTMS Repetitive transcranial magnetic stimulation (rTMS)
over the left dorsolateral prefrontal cortex has recently been
issued (Baptista et al. 2019) and posterior insula stimulation Three studies have been performed using high-frequency
was also shown to be ineffective (Galhardoni et al. 2019). rTMS over M1 in patients with fibromyalgia (Passard et al.
Overall, the level of evidence is higher for rTMS com- 2007; Mhalla et al. 2011; Boyer et al. 2014). Pain intensity
pared to tDCS (Lefaucheur et al. 2014), in part because the was reduced in two cases and quality of life was improved
amount of data is larger for rTMS than for tDCS, whose in the third study despite the absence of pain reduction. A
clinical trials began several years after rTMS ones. Only one weak recommendation for use was issued in 2016 (Cruccu
study was specifically designed to compare the analgesic et al. 2016) and a level A recommendation for high-fre-
effects of tDCS and rTMS in patients with chronic neuro- quency rTMS over M1 for fibromyalgia was issued recently,
pathic pain due to radiculopathy and rTMS was superior although identical data were analyzed in these two reviews
after three daily sessions (Attal et al. 2016). (Baptista et al. 2019).
Cost effectiveness has been proven to be in favor of rTMS
for the treatment of depression after the first treatment fail- Primary headaches
ure (Voigt et al. 2017). Such data are still lacking for chronic
pain and are awaited. TENS of the supraorbital nerve

Nociplastic pain Supraorbital nerve stimulation (SONS) is possible by

CEFALY©, which corresponds to a TENS device specifi-
Almost all the studies concerning this pain type have been cally developed to stimulate this terminal branch of the
performed in patients with fibromyalgia but burning mouth trigeminal nerve and which is applied on the forehead.
syndrome or vulvodynia also respond to the definition of Using a 20 min stimulation session daily, there was a clear
nociplastic pain. trend (decrease of 2.06 days/month in the active group ver-
sus 0.32 in the sham group, p = 0.054) for its efficacy in
Transcutaneous electric nerve stimulation (TENS) episodic migraine prevention (Schoenen et al. 2013b). A
recent study has also shown efficacy for acute pain treatment
One well-designed study suggested a potential benefit of during attacks (Chou et al. 2019). No sufficient evidence is
TENS in fibromyalgia, at least during the stimulation (Dai- currently available to support the efficacy of this device in
ley et al. 2013). Nonetheless, there is insufficient data to chronic migraine prophylaxis or other primary headaches.
date to support or refute the use of TENS for fibromyalgia Although confirmatory studies are still lacking, the major
(Johnson et al. 2017). advantage of this technique is its safety and ease of use.
As for other TENS devices, the exact mechanism of action
Transcranial direct current stimulation (tDCS) is unknown. Experimental data suggest direct action on
the central nervous system (Piquet et al. 2011; Magis et al.
The recent Latin American and Caribbean consensus on 2017).
non-invasive central nervous system neuromodulation for
chronic pain management (LAC2-NIN-CP) has provided Vagus nerve stimulation (VNS)
level A recommendations for anodal tDCS of M1 in fibro-
myalgia (Baptista et al. 2019). Indeed, four out of five stud- VNS was considered as a possible treatment for primary
ies conducted in that case showed at least some benefit headache following the description of migraine improve-
compared to placebo. Nonetheless, the effect size is quite ment by epileptic patients with migraine comorbidity, while
low. HD-tDCS has been tested with significant benefit in their epilepsy was treated by implanted VNS (Lenaerts et al.
a single controlled trial and an open-labeled study (Don- 2008). The recent development of devices for non-invasive
nell et al. 2015; Castillo-Saavedra et al. 2016). Level B VNS has increased interest in this target. Indeed, a specific
device (gammaCore©) has been developed for the treatment

13
Neurostimulation methods in the treatment of chronic pain

of primary headaches by non-invasive stimulation of the and reinforce the interest of cortical modulation in migraine
cervical branch of the vagus nerve. Such stimulation has treatment (Coppola et al. 2013).
been shown to reduce cortical spreading depression in ani- In a recent well-conducted systematic review, eight stud-
mal models (Chen et al. 2016). Further experimental work ies have been found concerning tDCS in migraine preven-
has shown a reduction in allodynia that was correlated with tion, seven of those showing a positive effect (Stilling et al.
a reduction in the extracellular glutamate concentration in 2019). Nonetheless, these studies were heterogeneous and
the pars caudalis of the spinal trigeminal nucleus (Oshinsky with very limited sample size, leading to a low GRADE
et al. 2014). quality and precluding any firm conclusion.
To date, there is some evidence for pain reduction dur-
ing migraine attacks when used within 20 min from pain Transcranial magnetic stimulation (TMS) and repetitive TMS
onset (Tassorelli et al. 2018). Results for chronic migraine (rTMS)
treatment were negative in a small study (Silberstein et al.
2016a). Concerning cluster headache, two case series have In the same systematic review, 16 studies concerning rTMS
been published, suggesting a potential interest to reduce and 6 concerning TMS were included (Stilling et al. 2019).
attacks frequency in chronic cluster headaches patients (Nes- The majority of rTMS studies reported reduction in head-
bitt et al. 2015; Marin et al. 2018). Nonetheless, the only ache frequency, duration, intensity, abortive medication use,
RCT published to date was negative and sub-group analysis depression, and functional impairment.
was in favor of an efficacy of such treatment in episodic CH Single pulse TMS was developed with the hypothetical
only (Silberstein et al. 2016b). Thus, although safe, evidence goal of modulating CSD (Ferrari et al. 2015). Such a modu-
for its use is still limited. Another major limit for its use lation was later confirmed on a mouse model demonstrat-
comes from its cost. Indeed, a device allowing 300 treat- ing in vivo that single pulse TMS over the occipital cortex
ment cycles of 2 min is sold around 550€ and it is proposed was able to block CSD (Andreou et al. 2016). Nonetheless,
to use 1 or 2 cycles, 3 times a day when used as preventive the same protocol was able to block CSD in only 25% of
treatment and 2 cycles at the attack onset when used as acute cats, which gyrencephalic cortex is more similar to the brain
treatment. cortex (Andreou et al. 2016). The production of a portable
and rechargeable medical device gives the opportunity to
realize single pulse TMS at home at the beginning of an
Remote electrical neuromodulation (REN)
attack. In a well-conducted trial involving 82 patients in
each group, 39% were pain-free at 2 h after device appli-
REN is a recent acute migraine treatment that stimulates
cation on the occiput and the administration of two stim-
upper arm peripheral nerves to induce conditioned pain
ulations as early as possible at the attack onset, whereas
modulation (CPM). CPM corresponds to the principle that
only 22% were pain-free in the control group (p = 0.0179)
pain inhibits pain, previously described in animals as diffuse
(Lipton et al. 2010). Two post-market evaluations of this
inhibitory control (Yarnitsky 2010). Indeed, an endogenous
device have been published, both reporting good efficacy
analgesic mechanism allows a conditioning stimulation to
and tolerance in migraineurs with or without aura (Bhola
inhibit pain in remote body regions. For REN, the central
et al. 2015; Starling et al. 2018). The adverse effects (dizzi-
inhibitory effect is induced using a well-felt but non-noxious
ness, tinnitus, worsening of migraine) have been of mild to
conditioning stimulus, such as heat at below pain thresh-
moderate intensity and transient. This device (SpringTMS©)
old, for CPM induction in healthy participants. Two recent
has a CE mark but is not supported by all health systems.
studies conducted by the same group showed that REN can
With medical prescription, it is available on the website of
significantly reduce headache pain during migraine attacks
the manufacturer for rent (230€ per month).
(Yarnitsky et al. 2017, 2019).
Many non-invasive brain stimulation techniques are
available for pain treatment. However, current techniques
Transcranial direct current stimulation (tDCS) for clinical use are all ‘open loop’, i.e., delivered accord-
ing to preprogrammed settings and unaffected by changes
As cortical spreading depression (CSD) is the support of in the patient’s clinical symptoms or recordable parameters.
the migraine aura and a possible trigger of migraine head- Closed-loop neurostimulation systems, which modulate or
ache, modulating cerebral cortex to reduce migraine has adapt therapy in response to physiological changes, are cur-
been proposed (Ferrari et al. 2015). In addition, several rently developed especially for epilepsy or movement dis-
electrophysiological studies have shown that migraine brain orders and may provide more effective therapy (Mansouri
was characterized by a lack of habituation of visual evoked et al. 2018; Levy et al. 2019). To date, most of the studies
potentials (Ambrosini et al. 2017). This abnormal processing for non-invasive therapies are limited by a relatively short
of the incoming information could be due to dysrhythmia follow-up and cost-effectiveness studies are lacking. It is

13
 X. Moisset et al.

also important to note that several therapies were evaluated (de Vos et al. 2009), 65% of the patients treated by SCS
without double blinding that is sometimes impossible (par- improved over 50% compared to 5% in the control group.
esthesia induced by stimulation devices). The pain intensity decreased by 4 points on the VAS in
average. In FBSS, about 50–60% of the patients reported
a decreased pain intensity > 50% after 1 year in large open
Invasive stimulation techniques series (Turner et al. 2004). In this indication, two RCTs
have shown that tonic SCS was significantly superior to best
Neuropathic pain medical treatment alone (Kumar et al. 2007, 2008) or to
repeated spine surgery (North et al. 2005), to alleviate lower
Spinal cord stimulation limb pain, in terms of pain score, responders rates, patient’s
satisfaction, quality of life and emotional impact. However,
Spinal cord stimulation (SCS), proposed since 1967 (Shealy in these studies, SCS was less effective on low back pain.
et al. 1967), consists of delivering a continuous electrical Recent technological innovations aimed to address low back
stimulation to the dorsal column of the spinal cord, using a pain, either using multicolumn leads to stimulate sensory
chronically and fully implanted device. The mechanism of fibers corresponding to the low back area (Buvanendran
action, initially based on the gate control theory (Melzack and Lubenow 2008) or using new stimulation modalities as
and Wall 1965), is still imperfectly known. SCS probably burst stimulation or high-frequency stimulation (Kinfe et al.
acts through inhibition of the nociceptive message trans- 2016). In non-inferiority studies, burst (Deer et al. 2018) and
mission and nociceptive neurons hyperactivity in the dorsal high-frequency (Kapural et al. 2016) stimulations were at
horn of the spinal cord and through supraspinal mechanisms least efficient than tonic SCS and were preferred by a major-
including activation of the inhibitory descending pathways ity of FBSS patients.
(Meyerson and Linderoth 2006). In less frequent indications such as peripheral nerve
The stimulation electrode is implanted, percutaneously injury, amputation, and post-herpetic neuralgia, few case
or surgically, in the posterior epidural space, in contact with series reported significant improvement in about 50% of the
the spinal cord. A trial stimulation phase, using an external patients. SCS is classically ineffective in pain secondary to
battery for a few days, is mandatory to assess the efficacy complete spinal section, brachial plexus avulsion and central
of the therapy (pain intensity decrease > 40–50%) before post-stroke pain (Cruccu et al. 2007). Most frequent com-
connecting the electrode to a subcutaneous stimulator. For plications are related to hardware dysfunction (migration,
more than 40 years, only tonic (50–90 Hertz) continuous disconnection, electrode breakage, etc.) that may require
stimulation, inducing perceptible paresthesia, has been used. additional surgery, or superficial infection (4.5%) (Turner
Recently, new stimulation modalities have been proposed, et al. 2004). The risk of spinal cord damage, either by direct
as burst stimulation, high-frequency (> 1000 Hertz) stimula- lesion or indirect compression by epidural hematoma, is
tion or high-density stimulation, to avoid the perception of exceptional.
paresthesia or increase the pain relief. Most of the health agencies recommend the use of SCS
SCS indications have been specified in several consensus in FBSS and CRPS, with recommendations for other neu-
recommendations (Gybels et al. 1998; Cruccu et al. 2007, ropathic pain varying across countries. The improvement
2016) and concern predominantly neuropathic pain with of pain is, however, rarely followed by the resumption of a
limited topography, excepting the face, after the failure of professional activity, which may be partly explained by the
conventional drug treatments. Most frequent indications usually too long delay between the onset of the painful situ-
are post-operative chronic low back and radicular pain (also ation and the time of the SCS procedure. Another important
called failed back surgery syndrome (FBSS)) (grade B rec- point is that SCS has been shown to be cost effective in the
ommendation), complex regional pain syndromes (CRPS) long term in FBSS (Hoelscher et al. 2017).
(grade B), and peripheral neuropathy pain (grade D). The
indication must be carried by an experienced multi-disci- Dorsal root ganglion stimulation (DRG stimulation)
plinary team as part of a comprehensive management of the
pain problem, including psychological evaluation and care. The dorsal root ganglion (DRG) is an interesting target for
Several randomized controlled trials (RCT) have demon- neuromodulation, because it plays a key role in neuropathic
strated SCS efficacy in different indications. In CRPS, SCS pain and participates in the phenomenon of peripheral and
associated with physiotherapy was significantly superior to central sensitization (Krames 2015). Experimental DRG
physiotherapy alone (Kemler et al. 2000), leading to an aver- electrical stimulation has been shown to reduce abnormal
age pain improvement of 3.5 points on the Visual Analogue activity of DRG neurons, which may be used to decrease
Scale (VAS). In an RCT comparing SCS and medical treat- neuropathic pain (Koopmeiners et  al. 2013). Chronic
ment to improve pain secondary to diabetic polyneuropathy DRG stimulation technique, based on percutaneous SCS

13
Neurostimulation methods in the treatment of chronic pain

technique, has been recently developed and consists of per- the most reliable method to select patients for EMCS (Pom-
cutaneous implantation of 1–3 epidural electrode(s) over the mier et al. 2018).
DRG in the foramen, at levels corresponding to the patient’s
painful area. A trial stimulation is performed before chronic Deep brain stimulation (DBS)
implantation of the generator.
DRG stimulation is mainly indicated in chronic neuro- In the 1970s and 1980s, DBS was commonly used for the
pathic pain of the inferior limb or trunk, localized in few treatment of chronic refractory pain (Bittar et al. 2005). Two
radicular territories, including CRPS, post-surgical or post- targets have been mainly used: the sensory thalamus (nuclei
zoster thoracic or inguinal pain. Compared to classical SCS, ventral posterior medial and lateral) contralateral to pain and
DRG stimulation seems to better capture discrete painful the periaqueductal grey (PAG)/periventricular grey (PVG).
areas such as the feet or the groin, to provide more stable Thalamic electrodes are implanted stereotactically according
paresthesia intensities across body positions (Liem et al. to somatotopy and location of pain, which usually requires
2013). In a recent non-inferiority study, DRG stimulation microelectrode recordings and stimulation to physiologically
has shown to be safe and efficient (even slightly superior) map the target. Stimulation (frequency 30–40 Hz, amplitude
than SCS to treat complex regional pain syndrome (CRPS) 2–5 V) of the sensory thalamus elicits paresthesia covering
in the lower extremities (Deer et al. 2017). the painful regions. Thalamic DBS probably acts by modu-
lating the altered firing patterns (bursting activity) observed
in the thalamus of chronic pain patients (Dostrovsky 2000).
Cortical stimulation The anti-nociceptive effect of PAG/PVG stimulation (1–5 V,
10–25  Hz) was reversed by naloxone (Hosobuchi et  al.
Epidural motor cortex stimulation (EMCS) has been pro- 1977), and likely related to the activation of the endogenous
posed since 1991 by Tsubokawa (Tsubokawa et al. 1991), opioid system.
based on the inhibitory effects of internal capsule stimula- Though no proper studies comparing the outcome of DBS
tion on thalamic hyperactivity in a cat model of neuropathic in different targets have been conducted, it is a general con-
pain. One or two epidural leads are implanted over the pre- sensus that stimulation of the sensory thalamus is indicated
central gyrus contralateral to the pain side, and then con- for neuropathic pain, whereas nociceptive pain responds bet-
nected to the generator. Usual stimulation parameters are: ter to PAG/PVG stimulation. In a meta-analysis of 6 series
frequency 30–90 Hz, amplitude 80% of the motor threshold, accounting for more than 400 patients, success rates were
and adapted to pain relief and tolerance (avoiding contrac- 63% and 47%, respectively, in nociceptive and neuropathic
tions and seizures). Unlike SCS, the patients do not perceive pain patients, 31% and 51% for pain from central and periph-
EMCS. Neuroimaging studies have shown brain activity eral origin, respectively (Bittar et al. 2005). Two industrial
changes in the thalamus, anterior cingulate, prefrontal cortex open-labeled studies have been interrupted for insuffi-
and brain stem during EMCS or following its discontinua- cient benefit and the company did not apply for marketing
tion (Peyron et al. 2007). Other studies suggested that EMCS approval to treat pain with DBS (Coffey 2001). Surgical
may act through release of endogenous opioids (Maarrawi complications of DBS for pain are similar to those of DBS
et al. 2007) and/or changes in pain and sensory detection for movement disorders: intracranial hemorrhage (2–3%,
thresholds (Fontaine et al. 2009a). Complications are rare: mostly asymptomatic), hardware dysfunction (4–5%), and
hardware infection (3%), hardware dysfunction, intracranial infection (3–5%).
hemorrhage (< 1%), epileptic seizures (during the stimula- Due to the lack of high-quality evidence, and the develop-
tion parameters setting, but no chronic epilepsy). ment of less dangerous alternative treatments, there has been
EMCS is indicated for neuropathic pain that cannot be a progressive decline in the number of chronic pain patients
treated by SCS, such as central post-stroke pain, or trigemi- treated with DBS within the last decades. However, DBS
nal neuropathy, and less frequently in pain following para- may still be considered as a therapeutic option in patients
plegia, brachial plexus avulsion and phantom limb pain. with medically refractory neuropathic pain who have basi-
EMCS efficacy has been studied mainly in short open series cally only two surgical options: EMCS or DBS.
(about 300 patients), reporting that about half of patients
improved over 40–50% (Fontaine et al. 2009b). A limited Primary headaches
comparative study reported a moderate but non-significant
pain improvement when the stimulator was switched on Invasive neuromodulation techniques have been proposed
versus switched off (Lefaucheur et al. 2009). EMCS can since 2000 to treat primary headaches including cluster
help, sometimes drastically, patients with severe pain, but headache (CH), other trigemino-autonomic cephalalgias
its efficacy is random and predictive criteria of response are (TACs) and chronic migraine. These techniques are based on
lacking. Multiple sessions of motor cortex rTMS might be the chronic or transient modulation of structures involved in

13
 X. Moisset et al.

the pathophysiology of these headaches, and include DBS of 2002), the improvement of CH patients after lesional pro-
the retro-hypothalamic area, chronic occipital nerve stimula- cedures targeting the SPG (Fontaine et al. 2018) and the
tion (ONS) and transient stimulation of the spheno-palatine possibility to experimentally stop CH attacks using acute
ganglion (SPG). SPG electrical stimulation (Ansarinia et al. 2010). SPGS is
supposed to act through parasympathetic inhibition, second-
Deep brain stimulation ary to the high-frequency stimulation and it has been shown
that, conversely, low-frequency SPGS was likely to trigger
DBS has been the first neuromodulation technique to be pro- CH attacks (Schytz et al. 2013).
posed in primary headaches and concerns only drug-refrac- A specific implantable device (­ Pulsante®, Autonomic
tory chronic cluster headache (CCH). The initial concept Technologies, USA) has been developed to deliver on-
was to inhibit (using high-frequency DBS) the presumed CH demand SPGS to abort CH attacks. This device is chroni-
attack generator, identified shortly before by neuroimaging cally implanted along the posterior wall of the maxillary
studies in a border area between the hypothalamus and the bone in the pterygopalatine fossa (PPF), fixed with a screwed
mesencephalon. Indeed, this area was activated specifically plate to the zygomatic process and the lead is in contact with
during CH attacks and showed structural abnormalities in the spheno-palatine ganglion. As the device contains no bat-
CH patients compared to controls (May et al. 1998, 1999). tery, a remote controller using radiofrequency energy is used
However, the neural structure(s) whose stimulation induces to deliver power trans-cutaneously and activate the stimula-
the therapeutic effect is still debated. Several candidates have tion. SPGS usually induces paresthesia in the soft palate.
been identified, including the mesencephalic grey substance, Evidence supporting SPGS by ­Pulsante® is limited to the
the ventral tegmental area and several tracts connecting the treatment of CH attacks. In a multicenter randomized sham-
hypothalamus with the trigeminal system and other brain- controlled study evaluating the safety and abortive efficacy
stem nuclei associated with nociception and pain modulation in CCH patients, pain relief was achieved in 67% of optimal
(Fontaine et al. 2010a; Akram et al. 2017). stimulation-treated attacks compared to 7% of sham treated
Based on the initial concept, Leone et al., proposed DBS (p < 0.0001). Absence of pain was achieved in 34% and 1.5%
targeting this region and treated successfully several patients of attacks after optimal stimulation and sham stimulation,
with refractory CCH (Leone et al. 2001). Up to now, con- respectively (p < 0.0001). 19 of 28 (68%) patients experi-
tinuous high-frequency (130 Hz) DBS has been studied enced a clinically significant improvement, but only 32%
only in open series (about 80 CCH patients), reporting that achieved a pain relief in more than 50% of the treated attacks
DBS acts like a preventive treatment by decreasing the CH (Schoenen et al. 2013a).
attack frequency [review in (Martelletti et al. 2013)]. About Long-term (24 months) results of the open extension
60% of the patients did respond to DBS (response being phase of this study reported that SPGS achieved pain relief
defined as a ≥ 50% decrease of attack frequency), includ- in 65% of CH attacks, with a delay of 11 min on average. 15
ing 30% of patients being almost pain-free at longer follow- out of 33 patients (45%) were considered as acute responders
up. A controlled study failed to demonstrate the efficacy of (at least 50% of attacks were successfully treated). Moreo-
this approach due to methodological issues (Fontaine et al. ver, 43% of the patients experienced a > 50% reduction in
2010b). attack frequency over time, suggesting that repeated use of
DBS is considered as the last-line preventive treatment SPG stimulation might act as a CH preventive treatment.
of the most severe CCH patients and should only be per- Nevertheless, this study was not designed to demonstrate
formed by experienced teams with respect to the following a preventive effect and spontaneous transformation from
selection criteria: at least 2 years of disease duration, at least chronic to episodic forms of the disease cannot be excluded.
one attack per day, resistance to pharmacotherapy including In a cohort of 99 patients (Assaf et al. 2016), the most fre-
verapamil and lithium, headache “locked” to the same side, quent (67%) surgical complication was V2 hypoesthesia usu-
normal neurological examination, and absence of psychiatric ally transient, 46% of them resolving within a mean delay of
comorbidity (Leone et al. 2004; Martelletti et al. 2013). This 3.5 months. Infection rate was 5%.
position as a last-line treatment is justified by the invasive- According to available evidence, SPGS should be dedi-
ness and the risks of DBS (intracranial hemorrhage). cated to the acute treatment of patients with chronic CH
and strictly lateralized attacks, especially those who do not
Spheno‑palatine ganglion stimulation (SPGS) respond to oxygen inhalation and subcutaneous sumatriptan
injection, and those with a high daily number of attacks since
Invasive stimulation of the spheno-palatine ganglion (SPG) the system allows a 5-min stimulation that can be repeated
has been proposed based on several arguments, including as many times as needed. SPGS might also be indicated in
the involvement of the parasympathetic system in the patho- episodic CH patients who suffer from long painful bouts, but
physiology of trigeminal autonomic cephalalgias (Goadsby evidence is lacking in this population.

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Neurostimulation methods in the treatment of chronic pain

Occipital nerve stimulation (ONS) the literature (Magis and Schoenen 2012), including about
350 patients studied in 3 RCTs, all of them comparing active
The principle of ONS is to deliver a continuous electri- ONS versus “sham” ONS in patients suffering from chronic
cal stimulation to the greater occipital nerve (GON) and/ migraine refractory to at least 2 preventive medical treatments.
or to the lesser occipital nerve (LON), via a subcutaneous Two of these studies concluded that the reduction of headache
chronically implanted electrode adjacent to the nerve and days and global pain was higher in the ONS group than in
connected to a generator. ONS has been originally proposed the control group, but the difference did not reach a statisti-
to treat occipital neuralgia (Weiner and Reed 1999) and few cal significance (Lipton et al. 2009; Saper et al. 2011). In the
series of cases suggest good efficacy in this indication, but last RCT, the responder rate, which was the primary endpoint,
ONS has been mainly used to treat primary headaches. did not differ significantly between groups, a response being
defined as a global pain decrease > 50% during the 3 month-
ONS in  cluster headache  The demonstration of ONS effi- randomized period (Silberstein et  al. 2012). However, there
cacy in controlled conditions is challenging because it was a significant reduction in headache days (− 3.0 days per
usually induces occipital paresthesia, which limits the month) and migraine-related disability between active and
double-blind evaluation. A double blind RCT is currently control groups. These results were confirmed on the 1-year
ongoing. Its innovative design, comparing high-intensity open extension phase of the study (Dodick et al. 2015). Based
(100%) ONS and “sham” low-intensity (30%) ONS, is pro- on these data, a company obtained a conditional CE mark in
posed to maintain double blinding (Wilbrink et  al. 2013). Europe for ONS in chronic migraine, but the CE mark was
Pending its results, the ONS efficacy of ONS in chronic resumed 2  years later due to a poor risk/benefit ratio in the
CH is only supported by open series (review in (Magis post-inscription registry. Consequently, this indication is still
and Schoenen 2012)). The overall success rate (attack fre- a matter of debate and is not approved by the FDA.
quency decrease > 50%) was 46–75% across series. ONS
acts like a prophylactic treatment, decreasing the CH Mechanisms of  action ONS exact mechanism of action
attacks’ frequency, intensity and duration. In a prospective remains a matter of debate. ONS probably acts through
study including 44 chronic CH sufferers treated by ONS modulation of the trigemino-cervical complex, namely the
with 1-year follow-up, the French ONS registry reported convergence of sensory inputs from C1–C2 roots on the
a 50% attack frequency reduction in 59%, whereas 40% nociceptive spinal trigeminal nucleus, by a “gate control
could reduce their preventive pharmacological treatment theory-like” mechanism (Goadsby et  al. 2008). However,
(Fontaine et  al. 2017). Moreover, the quality of life func- the delayed effect observed in many patients suggests a
tional and emotional impacts were dramatically improved more complex mechanism, likely non-specific to primary
in responders. Due to the lack of controlled conditions, an headaches. Several arguments suggest that ONS might act
eventual placebo effect cannot be ruled out, considering that through a non-specific regulation of the central pain control
such placebo effect may be seen in CH like in other primary systems rather than modulation of central generators of CH
headaches and that the natural history of CH is often char- or migraine attacks. First, some successfully ONS-treated
acterized by fluctuations and spontaneous remissions. Nev- chronic CH patients still report autonomic attacks with-
ertheless, two main elements in collected data suggest more out pain. Then, functional neuroimaging studies showed
than a placebo effect or a natural history: the preceding very that ONS induces metabolic changes in the “pain matrix”
long duration of the chronic phase in the implanted patients regions, especially in the anterior cingulate cortex, but no
and the rapid worsening and recovery after technical failures change in the presumed hypothalamic CH generator (Magis
which appear as a consistent finding across the series. et al. 2011) or the presumed migraine generator in the dorsal
The European Headache Federation has considered ONS pons (Matharu et al. 2004).
as a valuable therapeutic alternative in drug-refractory To date, most of the studies for invasive therapies were
chronic CH (Martelletti et al. 2013), a statement supported evaluated without double blinding, that is at least very dif-
by evidence and the benefit/risk ratio of this approach some- ficult to conduct, or even impossible (paresthesia induced
times considered as ‘minimally-invasive’. ONS complica- by stimulation devices). Apart from SCS, cost-effectiveness
tions are minor: infections, fast battery depletion (mean data are still lacking for these therapies.
battery life 1–2 years), lead migration (due to neck move-
ments) and other hardware dysfunction. Considering their
respective risks, ONS should be proposed before DBS in Conclusion
refractory CCH patients.
Various neurostimulation techniques are currently available
ONS in chronic migraine  About 500 patients suffering from for pain treatment, targeting either the peripheral or central
chronic migraine and treated by ONS have been reported in nervous system with non-invasive or invasive devices. Better

13
 X. Moisset et al.

selecting potential responders would be of major interest to action on pain subtypes. Neurology 71:833–840. https​://doi.
propose these therapies earlier to the right patients. Closed- org/10.1212/01.wnl.00003​25481​.61471​.f0
André-Obadia N, Mertens P, Lelekov-Boissard T et al (2014) Is life
loop devices are of potential interest to increase efficacy and better after motor cortex stimulation for pain control? Results
reproducibility, but further studies are needed before using at long-term and their prediction by preoperative rTMS. Pain
these techniques more extensively. Physician 17:53–62
Finally, it is important to keep in mind several limitations. Andreou AP, Holland PR, Akerman S et al (2016) Transcranial mag-
netic stimulation and potential cortical and trigeminothalamic
First, this review corresponds to a general overview and is mechanisms in migraine. Brain J Neurol 139:2002–2014. https​
not a systematic review. Thus, although large, this review is ://doi.org/10.1093/brain​/aww11​8
not exhaustive. In addition, non-invasive and invasive tech- Ansarinia M, Rezai A, Tepper SJ et al (2010) Electrical stimula-
niques have not been compared directly. To date, it has been tion of sphenopalatine ganglion for acute treatment of cluster
headaches. Headache 50:1164–1174. https​: //doi.org/10.111
shown that non-invasive techniques could have an interest- 1/j.1526-4610.2010.01661​.x
ing predictive value for response to invasive ones: rTMS Antal A, Alekseichuk I, Bikson M et al (2017) Low intensity tran-
for EMCS (Lefaucheur et al. 2011; André-Obadia et al. scranial electric stimulation: safety, ethical, legal regulatory
2014; Pommier et al. 2018) and possibly occipital TENS and application guidelines. Clin Neurophysiol. https​: //doi.
org/10.1016/j.clinp​h.2017.06.001
for ONS, but shown by a single team (Nguyen et al. 2016). Assaf AT, Hillerup S, Rostgaard J et al (2016) Technical and surgical
Direct comparisons of non-invasive and invasive techniques aspects of the sphenopalatine ganglion (SPG) microstimulator
together with conventional care are awaited, also including insertion procedure. Int J Oral Maxillofac Surg 45:245–254.
cost-effectiveness evaluations. https​://doi.org/10.1016/j.ijom.2015.09.023
Attal N, Ayache SS, Ciampi De Andrade D et al (2016) Repeti-
tive transcranial magnetic stimulation and transcranial direct-
current stimulation in neuropathic pain due to radiculopa-
Compliance with ethical standards  thy: a randomized sham-controlled comparative study. Pain
157:1224–1231. https​: //doi.org/10.1097/j.pain.00000​0 0000​
Conflict of interest  X Moisset has received personal fees from Teva, 00051​0
Novartis, Roche, Biogen, Sanofi-Genzyme and Merck-Serono, and Ayache SS, Palm U, Chalah MA et al (2016) Prefrontal tDCS decreases
non-financial support from SOS oxygene, Boehringer, Bristol My- pain in patients with multiple sclerosis. Front Neurosci 10:147.
ers Squibb, not related to the submitted work. M. Lanteri-Minet  re- https​://doi.org/10.3389/fnins​.2016.00147​
ceived grants and honoraria for advisory boards, speaker panels or Baptista AF, Fernandes AMBL, Sá KN et al (2019) Latin American
investigation studies from Allergan, Amgen, Astellas, ATI, BMS, and Caribbean consensus on noninvasive central nervous system
Boehringer,  Boston Scientific, CoLucid, Convergence, GlaxoSmith- neuromodulation for chronic pain management (LAC2-NIN-CP).
Kline, Grunenthal, Eli Lilly,  Medtronic,  Menarini, MSD, Novartis, Pain Rep 4:e692. https​://doi.org/10.1097/PR9.00000​00000​00069​2
Pfizer, Reckitt Benckiser,  Saint-Jude-Abbott, Sanofi-Aventis, Teva Bhola R, Kinsella E, Giffin N et al (2015) Single-pulse transcranial
Pharmaceuticals, UCB, and Zambon. D Fontaine has received per- magnetic stimulation (sTMS) for the acute treatment of migraine:
sonal fees from Boston Scientific, Medtronic and Saint-Jude-Abbott. evaluation of outcome data for the UK post market pilot pro-
Boston Scientific, Medtronic and Saint-Jude-Abbott are in the field of gram. J Headache Pain 16:535. https​://doi.org/10.1186/s1019​
neuromodulation. 4-015-0535-3
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