revue neurologique 176 (2020) 325–352

Available online at

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Practice guidelines

Pharmacological and non-pharmacological

treatments for neuropathic pain: Systematic review
and French recommendations

X. Moisset a,b,*, D. Bouhassira c,d, J. Avez Couturier e, H. Alchaar f,

S. Conradi g, M.H. Delmotte h, M. Lanteri-Minet a,i, J.P. Lefaucheur j,k,
G. Mick l, V. Piano m, G. Pickering a,n, E. Piquet i, C. Regis o, E. Salvat p,
N. Attal c,d
a
Université Clermont Auvergne, Inserm, Neuro-Dol, 63000 Clermont-Ferrand, France
b
CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, France
c
INSERM U987, CETD, Ambroise-Paré Hospital, AP–HP, Boulogne-Billancourt, France
d
Université Versailles – Saint-Quentin-en-Yvelines, Versailles, France
e
Service de Neuropédiatrie, Consultation Douleur Enfant, CIC-IT 1403, CHU de Lille, Lille, France
f
73, boulevard de Cimiez, Nice, France
g
CETD, CHRU de Nancy, Vandœuvre-lès-Nancy, France
h
GHU, Paris site Ste-Anne, Structure Douleurs, 1, rue Cabanis, Paris 14, France
i
Département d’Évaluation et Traitement de la Douleur, Centre Hospitalier Universitaire (CHU) de Nice, Fédération
Hospitalo-Universitaire InovPain, Université Côte d’Azur, Nice, France
j
EA 4391, Faculté de Médecine, Université Paris Est Créteil, Créteil, France
k
Service de Physiologie, Explorations Fonctionnelles, Hôpital Henri-Mondor, Assistance publique–Hôpitaux de Paris,
Créteil, France
l
Centre d’Évaluation et Traitement de la Douleur du Voironnais, Centre Hospitalier de Voiron, Laboratoire P2S,
Université de Lyon, Lyon, France
m
Centre Hospitalier de Draguignan, Service Algologie 4e, route de Montferrat, 83007 Draguignan cedex, France
n
Clinical Pharmacology Department, CPC/CIC Inserm 1405, University Hospital CHU, Clermont-Ferrand, France
o
CETD, CHU Montpellier, Montpellier, France
p
Centre d’Évaluation et de Traitement de la Douleur, Hôpitaux Universitaires de Strasbourg, Université de
Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique,
Strasbourg, France

* Corresponding author at: Service de Neurologie, 58, rue Montalembert, 63000 Clermont-Ferrand, France.
E-mail address: xavier.moisset@gmail.com (X. Moisset).
https://doi.org/10.1016/j.neurol.2020.01.361
0035-3787/# 2020 Elsevier Masson SAS. All rights reserved.
326 revue neurologique 176 (2020) 325–352

info article abstract

Article history: Neuropathic pain remains a significant unmet medical need. Several recommendations
Received 23 November 2019 have recently been proposed concerning pharmacotherapy, neurostimulation techniques
Accepted 7 January 2020 and interventional management, but no comprehensive guideline encompassing all these
Available online 7 April 2020 treatments has yet been issued. We performed a systematic review of pharmacotherapy,
neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or
Keywords: central neuropathic pain, based on studies published in peer-reviewed journals before
Neuropathic pain January 2018. The main inclusion criteria were chronic neuropathic pain for at least three
Systematic review months, a randomized controlled methodology, at least three weeks of follow-up, at least 10
Randomized controlled trials patients per group, and a double-blind design for drug therapy. Based on the GRADE system,
Recommendations we provide weak-to-strong recommendations for use and proposal as a first-line treatment
Pharmacotherapy for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for
Neurostimulation topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral
Surgery neuropathic pain; a weak recommendation for use and proposal as a second-line treatment
Psychotherapy for pregabalin, tramadol, combination therapy (antidepressant combined with gabapenti-
noids), and for high-concentration capsaicin patches and botulinum toxin A specifically for
peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line
treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back
surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence
of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recom-
mended as a second-line therapy, as an add-on to other therapies. An algorithm encom-
passing all the recommended treatments is proposed.
# 2020 Elsevier Masson SAS. All rights reserved.

1. Introduction patients or elderly individuals with neuropathic pain. In

Neuropathic pain, caused by a lesion or disease affecting the
somatosensory nervous system, has a considerable impact on
quality of life and is associated with a high economic burden
on the individual and society [1–4].
Epidemiological surveys have shown that many patients
with neuropathic pain do not receive appropriate treatment
for their pain [2,5–9]. This may be due to a lack of diagnostic
accuracy, insufficient understanding of the pathophysiologi-
cal mechanisms of pain, relatively ineffective drugs and
insufficient knowledge of the effective drugs and their
appropriate use in clinical practice. Other non-pharmacolo-
gical treatments, including noninvasive neurostimulation
techniques, psychotherapy, complementary therapy and
invasive approaches, are increasingly being offered to patients
with neuropathic pain, most of whom are treated with a
combination of therapeutic approaches in routine clinical
practice [10,11]. However, recommendations for the treatment
of neuropathic pain have always been restricted to a specific
type of treatment, such as pharmacotherapy or neurostimula-
tion. Thus, for example, the previous French guidelines for
neuropathic pain treatment published in 2010 [12] focused
principally on pharmacotherapy. Since the publication of
these guidelines, international evidence-based recommenda-
tions have been issued for pharmacotherapy [13], interven-
tional management [14] and central neurostimulation [15]. No
evidence-based recommendations encompassing all the
available therapeutic approaches have yet been proposed
for neuropathic pain. Furthermore, most of the previous
recommendations considered adults, but not pediatric
France, neuropathic pain management in children is currently
governed by the guidelines published by the French regulatory
authorities for drugs in 2009 [16], which are mostly based on
adult guidelines and expert consensus.
Here, we aimed to propose new French recommendations
encompassing all the available therapeutic options for
neuropathic pain. We used the Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) system
[17,18] to propose a comprehensive therapeutic algorithm
encompassing all medical, psychological and surgical thera-
pies for neuropathic pain. We performed a systematic review
of randomized comparative or placebo-controlled trials with a
double-blind design, but we extended our search to single-
blind or open-label trials for treatments for which double
blinding is difficult or impossible, such as psychotherapy and
surgery. For topical and oral pharmacotherapies, we searched
for articles published since June 2013, making use of the most
recent systematic review and meta-analysis of pharmaco-
therapy jointly directed by one senior member of our group
[13] for older articles, and, for other therapies, we searched for
articles published since 1966 (first studies published in
MEDLINE). Disease-modifying treatments and specific treat-
ments for trigeminal neuralgia or erythromelalgia are beyond
the scope of this work [19].
2. Methods
This systematic review (PROSPERO CRD42019140749) was
prepared under the auspices of the International Association
 revue neurologique 176 (2020) 325–352
for the Study of Pain (IASP) French Chapter (‘‘Société française
pour l’étude et le traitement de la douleur’’, SFETD) and the
French Society of Neurology (‘‘Société française de neurolo-
gie’’, SFN) and supported by ‘‘Association nationale pédago-
gique des enseignants en thérapeutique’’, APNET (‘‘French
college of therapeutic teachers’’). We followed the 23-item
Appraisal of Guidelines for Research and Evaluation (AGREE II)
Instrument for the development and reporting of recommen-
dations [20]. Details of the search criteria and methods can be
found in Appendix 1. The guidelines proposed by the French
health authority (‘‘Haute Autorité de santé’’) were applied
(‘‘Recommandations pour la pratique clinique’’, [21]). The
steering group consisted of 15 healthcare professionals
(Appendix 2). A reading committee of 32 healthcare pro-
fessionals from the SFETD, SFN, other independent reviewers
and patients (‘‘Association francophone pour vaincre les
douleurs’’; AFVD) was set up and scored the proposals
(Appendix 2). This work was supported by a grant from SFN.
2.1. Procedures
The systematic literature review was performed according to
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statements [22]. We used a standar-
dized review and data extraction protocol (Appendix 3).
Randomized controlled trials (RCTs) published as full reports
in peer-reviewed journals until January 18, 2018 were
identified with PubMed/MEDLINE and Embase. We searched
for studies on oral or topical drug treatments published since
June 2013. For studies published from 1966 to June 2013, we
referred to the most recent systematic review (SR) and meta-
analysis on this subject, which was published in 2015 [13],
used the GRADE system, had similar inclusion criteria and was
jointly directed by the senior author of this study (NA). For all
other treatments, we searched for articles published since
1966 (these treatments included oral ketamine, intrathecal
therapy, IV drugs, nerve blocks, neurostimulation, surgery or
psychotherapy). Additional articles were identified from
published reviews (especially Cochrane reviews), the refe-
rence lists of the selected papers and additional searches of
the same databases for publications appearing up to August
2019.
The target population was patients of any age, including
children, with neuropathic pain according to the IASP
definition (pain caused by a lesion or disease of the
somatosensory nervous system), consistent with that used
for the 2015 meta-analysis [13]. The neuropathic pain
conditions considered included postherpetic neuralgia, dia-
betic and non-diabetic painful polyneuropathy, post-amputa-
tion pain, post-traumatic/postsurgical neuropathic pain
including plexus avulsion and complex regional pain syn-
drome type II (post-traumatic/postsurgical neuropathic pain),
central post-stroke pain, spinal cord injury (SCI) pain, and
multiple sclerosis-associated pain. Multiple etiologies of
neuropathic pain were considered. Neuropathic pain associa-
ted with nociceptive components (e.g. cancer neuropathic
pain and radiculopathy) was included provided that the
neuropathic pain was considered separately. Conditions such
as complex regional pain syndrome type I, low back pain
without radicular pain, fibromyalgia, and persistent idiopathic
327
facial pain were not included, because they do not fulfill the
current definition of neuropathic pain. Trigeminal neuralgia
was excluded because of generally distinct response to drug
treatment.
The main inclusion criteria common to all treatment
groups were: chronic neuropathic pain (for at least 3 months);
single (e.g. iv drugs) or repeated administrations of treatment;
randomized design; comparison with a control group (placebo
or comparator) over a follow-up period of at least three weeks
(i.e. at least three weeks of assessment of the efficacy of active
treatment and of comparator in the case of crossover trials); at
least 10 patients per group; pain assessed as a primary
outcome; studies published as full reports; any treatment for
neuropathic pain, regardless of label, available for use in
France. We anticipated significant heterogeneity in trial
quality. We therefore required a double-blind design for
studies of pharmacotherapy, radiofrequency and noninvasive
brain neurostimulation, but we extended our search to single-
blind or open-label controlled studies for TENS, invasive
neurostimulation, surgery, psychotherapy and hypnosis,
because double-blind studies were rare for these treatments
(mostly due to the difficulty achieving blinding for these
treatments). For example, TENS and conventional spinal cord
stimulation induce paresthesia in the painful area, so it is
difficult to blind the patient to the treatment group.
2.2. Evidence summary and reporting
We used the GRADE system (Appendix 4) to assess the risk of
bias for individual studies and groups of studies and to
propose recommendations.
2.2.1. Risk of bias in individual trials
Two review authors for each treatment independently
assessed the risk of bias for each study using the GRADE
system for individual studies. The methods are described in
detail in Appendix 4. We assessed the following for each study:
 random sequence generation (checking for possible selec-
tion bias) and allocation concealment;
 blinding of participants (checking for possible performance
bias);
 blinding of personnel;
 incomplete outcome data (checking for possible attrition
bias due to the amount, nature, and handling of incomplete
outcome data);
 statistical methods;
 sample size calculation;
 selective reporting;
 carryover effect, evaluated for crossover studies and noted
as ‘‘not applicable’’ for parallel group studies;
 the presence of any other bias evaluated separately,
including small sample size or poor description of neuropa-
thic pain definition in particular.
The overall quality of the study was considered ‘‘very high’’
if no bias was noted, ‘‘high’’ if there were only one or two
biases, ‘‘moderate’’ in the presence of three or four biases and
‘‘low to very low’’ if there was five or more biases. This
328 revue neurologique 176 (2020) 325–352
classification differs slightly from that used in previous
systematic reviews of neuropathic pain treatments [13,15] in
which the ‘‘low’’ and ‘‘very low’’ levels were generally
considered separately. Indeed, it was often difficult to
distinguish between trials of low and very low-quality, and
we felt that pooling these two levels together would be
unlikely to affect our recommendations (we did not recom-
mend treatments for which there was a low or very low level of
evidence for use).
2.2.2. Risk of bias across studies
Heterogeneity, imprecision, small effect size and indirectness
were evaluated with the GRADE system for a group of studies
(see Appendix 4 for detailed methods). These factors led to the
downgrading (when present) or upgrading (for the opposite
situation, e.g. large effect sizes) of the quality of evidence for a
group of studies. The risk of publication bias was not
specifically evaluated because no systematic search for
unpublished trials was performed.
The GRADE system was also used to propose recommen-
dations based on a group of RCTs pertaining to the same drug
class or technique. Final recommendations, based on the
GRADE system, were rated as strongly in favor of the
treatment, weakly in favor of the treatment, strongly or
weakly against the treatment, or inconclusive. These levels of
recommendations were based on the balance between efficacy
and adverse effects, patient satisfaction (if data were
available), and on prior evidence provided by the most recent
systematic review of oral and topical pharmacotherapy [13].
2.3. Outcome measures
We did not conduct a meta-analysis for this systematic study.
Instead, we report the number needed to treat (NNT) for a 50%
decrease in pain intensity (or alternatively, a 30% decrease in
pain intensity or at least moderate pain relief) and/or the effect
size for individual trials, to obtain an estimate of the
magnitude of effects on the primary outcome (pain intensity),
if such data were available. In tables (Appendix 5), efficacy was
assessed on the basis of effect size, absolute difference
between active and placebo or sham, or NNT. Effects on other
outcome measures such as neuropathic symptoms and signs,
sleep, quality of life, comorbidities, and Clinical Global
Impression of Change score, were reported when relevant
(for example, if no efficacy was observed for the primary
outcome measure), but were considered secondary. Serious
and common (> 10% incidence) reported adverse events and
dropouts due to adverse effects were recorded (Appendix 5).
2.4. Therapeutic algorithm
We developed a therapeutic algorithm for first-, second- and
third-line treatments for all the pharmacological and non-
pharmacological treatments available in France, with a
‘‘strong’’ or ‘‘weak’’ recommendation in favor of use based
on the GRADE system applied to all studies published since
1966 (studies of oral and pharmacotherapy published before
June 2013 being assessed in the meta-analysis of Finnerup
et al., 2015). The level of recommendation in the algorithm also
took into account ease of use and long-term experience with
the treatment, and was based on expert consensus for
conditions for which high-quality trials were lacking, for
elderly or pediatric populations, for example. These recom-
mendations do not take treatment costs into account because
these costs may differ from country to country and may
change over time. For the same reasons, the indications
proposed by regulatory agencies for use in neuropathic pain
were not taken into account.
3. Results
3.1. Study selection and characteristics
The results of the database and registry search are shown in
Fig. 1A for pharmacological treatments and Fig. 1B for non-
pharmacological therapies. We included a total of 131
published articles in the quantitative analysis. The characte-
ristics of the studies concerned are summarized in
Appendix 5.
Eligible studies investigated:
 pharmacological treatments: antidepressants, antiepileptic
agents, opioids, topical agents (mostly lidocaine and cap-
saicin), subcutaneous botulinum toxin type A (BTX-A),
combination therapy, cannabinoids, oral ketamine, intra-
venous drugs (e.g. ketamine, lidocaine, opioids, other),
intrathecal drugs (e.g. morphine, clonidine, local anesthe-
tics, ziconotide), nerve blocks, newer drugs;
 noninvasive peripheral stimulation (including TENS), inva-
sive peripheral stimulation, invasive and noninvasive
central neurostimulation, pulsed radiofrequency and other
surgical procedures;
 psychotherapies and other non-pharmacological treat-
ments not listed above.
Overall, 47% (n = 61) of all the trials considered concerned
diabetic painful polyneuropathy (DPN) or postherpetic neural-
gia (PHN); 11% (n = 14) concerned central pain, and 42%
concerned other neuropathic conditions (traumatic, radicular,
HIV, chemotherapy-induced, mixed etiologies). Few studies
lasted longer than 12 weeks, and the longest study duration
for the trials included was 24 weeks.
3.2. Oral and topical drug therapy
We used the results of the previous systematic review (SR)
[13], which considered studies published from 1966 to June
2013, and new studies published after this date in the
assessment of oral and topical drug treatments (except for
oral ketamine).
3.2.1. Antidepressants
We identified 18 low- to high-quality placebo-controlled trials
of tricyclic antidepressants (TCAs) (16 positive) in neuropathic
pain published before June 2013, with a final moderate quality
of evidence. TCAs (nortriptyline and imipramine) were studied
in two more recent high-quality RCTs of combination therapy
(125 patients treated) [23,24]. Each of the two drugs from the
 revue neurologique 176 (2020) 325–352 329

Fig. 1 – A. PRISMA flowchart for pharmacological treatments. B. PRISMA flowchart for non-pharmacological interventions.
Studies comparing different treatments can be included more than once in the flowchart. ADs: antidepressants; AEDs:
antiepileptic drugs; Canna: cannabinoids; keta: ketamine; lido: lidocaine; BTX: botulinum toxin; IV: intravenous; IT:
intrathecal. TENS: transcutaneous electrical nerve stimulation; rTMS: repetitive transcranial magnetic stimulation; tDCS:
transcutaneous direct current stimulation; SCS: spinal cord stimulation; EMCS: epidural motor cortex stimulation; PRF:
pulsed radiofrequency; CBT: cognitive behavioral therapy; DRG stim: dorsal root ganglion stimulation.

combination was superior to placebo when administered as a Nine placebo-controlled trials of duloxetine (seven yielding
monotherapy. The adverse effects reported included central positive results) and four placebo-controlled trials of venlafa-
and anticholinergic effects. The final quality of evidence was xine ER (two yielding positive results) in neuropathic pain were
high. published before June 2013, with a high-quality of evidence.
330 revue neurologique 176 (2020) 325–352
We identified five more recent RCTs of duloxetine (60–120 mg/
day; 565 with active treatment and 566 controls including 415
placebos) including three high-quality placebo-controlled trials
[25–27] and two comparative trials versus nortriptyline (low-
quality trial) or pregabalin (high-quality trial) [23,28]. Diabetic
painful neuropathy was the most frequent pain condition
among the patients studied. The placebo-controlled trials
yielded positive results for the primary outcome and for most
secondary outcomes, including sleep, mood and quality of life,
with a small effect size in the two largest studies and a large
effect size in a single-center study on lumbar radiculitis [27].
The two comparative studies concluded that duloxetine was
non-inferior to nortriptyline or pregabalin. The most frequently
reported adverse effects were nausea, loss of appetite,
somnolence, asthenia and dry mouth. One study in patients
with multiple sclerosis [25] found that discontinuation rates
were higher for duloxetine than for placebo. All these studies
were in favor of the use of duloxetine, with a high final quality
of evidence. There was no recent RCT for venlafaxine.
Recommendation: SNRIs (duloxetine and venlafaxine)
and TCAs have a strong recommendation for use in
neuropathic pain (high final quality of evidence), and
duloxetine should be preferred over venlafaxine (more
high-quality trials yielding positive results). TCAs should
be monitored carefully if used at high doses (> 75 mg
daily) because of potential risks of hypotension and
cardiac toxicity. Lower doses should be preferred.
3.2.2. Antiepileptic drugs
We identified 14 placebo-controlled trials of gabapentin (nine
yielding positive results) and six RCTs of gabapentin ER or
enacarbil (four yielding positive results) published before June
2013, with a high final quality of evidence. Three more recent
high-quality double-blind trials evaluated the efficacy of gaba-
pentin or gabapentin enacarbil/ER against peripheral neuropa-
thic pain (132 patients treated). One comparative trial showed
gabapentin to be superior to pregabalin, with fewer side effects
(see the section on ‘‘pregabalin’’), another showed gabapentin
enacarbil and gabapentin to be similarly effective against
postherpetic neuralgia [29], and one placebo-controlled trial of
gabapentin ER gave negative results for failed back surgery
syndrome with predominant neuropathic pain [30]. These recent
studies suggest that gabapentin is effective but are inconclusive
for gabapentin ER. The final quality of evidence was high.
We identified 25 placebo-controlled trials of pregabalin (18
yielding positive results) published before June 2013, with a
high final quality of evidence. We identified 14 more recent
high-to-very high-quality RCTs for pregabalin (150–600 mg/
day; 2101 patients treated) in the context of peripheral
neuropathic pain, mostly due to diabetic polyneuropathy,
including 12 placebo-controlled trials in which pregabalin
efficacy was primary outcome or pregabalin was an active
comparator (secondary outcome) (Appendix 5). Only two of the
eight trials considering pregabalin efficacy as the primary
outcome yielded positive results (137 patients treated). Two
studies gave results that were close to significance (588 patients
treated): in one, the results became significant if one patient
was excluded [31] and in the other, a long-term trial (15 weeks),
positive results were obtained at all earlier time points [32]. All
but one of the trials (the exception being a trial in which
pregabalin was an active comparator) were characterized by
very small effect sizes and/or large NNTs, with high rates of
placebo response. Potential confounding factors decreasing
efficacy included the use of moderate doses of pregabalin in
most trials (300 mg/day, although this dose is similar to that in
routine use), the inclusion of patients with refractory condi-
tions [33] and large carryover effects [34,35]. One recent double-
blind study comparing pregabalin (150 to 300 mg) to gabapentin
(1800 to 2400 mg) in chronic sciatica found that pregabalin was
significantly less effective than gabapentin (difference from
baseline: 1.72 for gabapentin versus 0.94 for pregabalin) [36].
Adverse effects, mostly dizziness and drowsiness, were
common, and were significantly more frequent than for
gabapentin in the comparative trial in patients with sciatica
(81% versus 19%) [36]. No severe side effects were reported.
These recent studies generally supported a lack of efficacy of
pregabalin, with a high final quality of evidence.
Studies published before our search date for other anti-
epileptic drugs yielded negative or inconclusive results. One
recent single-center placebo-controlled trial assessed oxcar-
bazepine in a population of patients with peripheral neuropa-
thic pain stratified for phenotype [37]; significant efficacy was
reported for the drug only in patients from the ‘‘irritable
nociceptor’’ group (limited thermal deficit in the painful area);
patients with burning and paroxysmal pain (according to the
NPSI questionnaire) were also more responsive to the active
drug. However, this study had several biases (Appendix 5),
including a high dropout rate and potential unblinding (most
patients recognized the active treatment because of adverse
effects). One recent small placebo-controlled study in patients
with painful small-fiber neuropathy related to Nav1.7 muta-
tion (n = 24) reported positive results for lacosamide [38]. The
final quality of evidence was low.
Recommendation: Gabapentin has a strong recommen-
dation for use in neuropathic pain (high final quality
based on new evidence and trials published before our
search date). The recommendation for the use of pre-
gabalin is weak, as most recent high-quality trials have
yielded negative results, with a balance between efficacy
and adverse effects lower than that for gabapentin, based
on a high-quality comparative trial. The evidence for the
use of other antiepileptics is inconclusive, although
oxcarbazepine and lacosamide may be beneficial for
small selected subgroups of patients (low-quality of evi-
dence). Based on our inclusion criteria, we found no data
concerning clonazepam [39] in neuropathic pain. This
does not rule out a potential efficacy of clonazepam on
pain paroxysms as reported in open-label uncontrolled
studies [40] and might have a clinical interest in case of
noctural awakening by the pain.
 revue neurologique 176 (2020) 325–352
3.2.3. Opioids
We identified 13 placebo-controlled trials of strong opioids
(mostly morphine and oxycodone, with 10 trials yielding
positive results) and seven placebo-controlled trials of
tramadol (all yielding positive results) published before June
2013, with a moderate final quality of evidence. We also
identified two controlled trials of the opioid agonist and
norepinephrine reuptake inhibitor tapentadol (one yielding
weakly positive results), with a low-quality of evidence. We
also found six additional placebo-controlled or comparative
studies of opioids (transdermal buprenorphine, fentanyl
patch and tapentadol) in 683 patients, one of which assessed
neuropathic pain in a heterogeneous group of patients with
pain. One of these studies was a high-quality placebo-
controlled study of transdermal buprenorphine in diabetic
painful neuropathy, which yielded negative results for the
primary outcome [in the intention-to-treat (ITT) population],
but positive results for most secondary outcomes, including
efficacy in the per protocol population [41]. One moderate-
quality placebo-controlled study of fentanyl one-day patches
for chronic pain yielded positive results for the primary
outcome, but negative results in patients with a neuropathic
pain component [42,43]. One study on tapentadol with an
enriched enrollment design yielded positive results for
diabetic painful neuropathy, with a small effect size (NNT
9.1) [44], and a moderate-quality double-blind comparative
study reported similar efficacies for 500 mg/day tapentadol
monotherapy and a combination of tapentadol (300 mg/day)
and pregabalin (300 mg/day) in patients with low back pain
with a neuropathic component [45]. The results of these
recent studies were inconclusive for buprenorphine and
fentanyl, and favored the use of tapentadol with a moderate
final quality of evidence. No recent RCT of tramadol was
identified.
Recommendation: Strong opioids (particularly morphine
and oxycodone) and tramadol have a weak recommen-
dation for use in neuropathic pain (based on studies
published before our search date). The evidence for
buprenorphine and fentanyl is inconclusive (moderate-
quality trials). Tapentadol has a weak recommendation
for use in peripheral neuropathic pain (moderate final
quality of evidence).
3.2.4. Topical agents
We identified three placebo-controlled studies of 5% lidocaine
plasters (one yielding positive results) published before June
2013, with a low final quality of evidence. Three more recent
high-quality placebo-controlled RCTs assessed lidocaine
plasters (250 patients treated) in patients with postsurgical
or multiple-etiology neuropathic pain [46–48]: two of these
studies [46,48] yielded positive results. Pickering et al. reported
positive effects of lidocaine patches on mechanical and cold
allodynia after nerve surgery (the primary outcome in this
study). The largest (multicenter, 180 treated patients and 183
controls) study [47] on postsurgical neuropathic pain gave
331
negative results for the primary outcome, but included several
confounding factors (Appendix 5). Two of the three studies
concluded that lidocaine plasters had a positive effect in
patients with peripheral localized neuropathic pain, particu-
larly those with allodynia, with a moderate final quality of
evidence.
We identified seven placebo-controlled studies of high-
concentration capsaicin patches (five yielding positive
results) and 11 studies of low-concentration capsaicin cream
(seven yielding positive results) for peripheral neuropathic
pain published before June 2013, with a high final quality of
evidence for high-concentration capsaicin patches and a
low-quality of evidence for low-concentration capsaicin
patches. We identified four more recent RCTs (351 patients
treated) of topical capsaicin in peripheral neuropathic pain:
two moderate-quality non-inferiority trials reported similar
effects for low-concentration (0.025% to 0.075%) capsaicin
cream and for topical clonidine or amitriptyline [49,50]; one
moderate-quality semi-double-blind placebo-controlled
study showed that low-concentration (0.625%) capsaicin
patches were superior to placebo, whereas high-concentra-
tion (1.25%) patches were not [51]; one high-quality study of
high-concentration capsaicin (8%) patches yielded positive
results, albeit with a modest effect size (7% absolute
difference in daily pain scores) in diabetic painful neuropa-
thy [52]. In all these studies, the placebo patches were
identical in appearance to the patches delivering active
treatment, but it was not possible to guarantee patient
blinding because skin reactions frequently occur with
capsaicin. These recent data suggest that high-concentra-
tion capsaicin patches are effective against diabetic peri-
pheral neuropathic pain, with a moderate final quality of
evidence, whereas the results for low-concentration cap-
saicin cream or patches are inconclusive.
Three moderate-quality studies [53–55] and one low-
quality study [56] yielded positive results for herbal prepara-
tions or nitroglycerin. One high-quality study on topical
ketamine yielded negative results for multiple-etiology peri-
pheral neuropathic pain [57]. The final quality of evidence was
low.
Recommendation: High-concentration capsaicin pat-
ches have a weak recommendation for use in peripheral
neuropathic pain, including diabetic neuropathic pain
(high-quality of evidence, but low effect size). The rec-
ommendation for the use of topical lidocaine in periph-
eral neuropathic pain is weak (moderate quality of
evidence but excellent safety profile). The evidence for
the use of capsaicin at low concentrations, herbal pre-
parations, nitroglycerin, clonidine and topical ketamine
is inconclusive.
3.2.5. Botulinum toxin A
We identified five low- to moderate-quality placebo-control-
led trials of subcutaneous (SC) botulinum toxin A in peripheral
neuropathic pain published before June 2013 (all five yielding
332 revue neurologique 176 (2020) 325–352
positive results, plus one large unpublished trial yielding
negative results). Three more recent placebo-controlled
studies assessed the use of SC botulinum toxin A in peripheral
neuropathic pain or spinal cord injury pain (74 patients
treated). One of these studies was of low-quality and the other
two were of high- to very high-quality, and all yielded positive
results [58,59]. The highest quality study found that the
presence and severity of allodynia and residual intraepider-
mal nerve fiber density on skin punch biopsy predicted the
response to BTX-A and that this drug was also particularly
effective against mechanical allodynia and paroxysmal pain
[59]. The other high-quality RCT showed that BTX-A was
effective against below-level spinal cord injury pain [60]. These
two recent studies support the efficacy of BTX-A against
neuropathic pain, with a high final quality of evidence.
Recommendation: Despite two recent positive high-
quality trials, the recommendation for SC botulinum
toxin A in peripheral neuropathic pain remains weak,
due to the paucity of high-quality large-scale studies.
3.2.6. Combination therapy
We identified 13 RCTs of combination therapy in neuropathic
pain (10 positive) published before June 2013, including three
high-quality studies highlighting the relevance of combining
pregabalin with duloxetine, or gabapentin with opioids or
TCAs for the treatment of neuropathic pain. We identified
three more recent double-blind RCTs of combination therapy,
two of which included TCAs (108 patients). One high-quality
study found that the combination of nortriptyline with
morphine at moderate doses was more effective than
monotherapy at higher doses for the treatment of peripheral
neuropathic pain [23,24]. Both these studies concluded that
the combination of TCAs with morphine or pregabalin was
more effective than monotherapy, with a high final quality of
evidence. One small double-blind active comparative study (14
patients per group) reported similar efficacies for methadone,
oral ketamine and their combination in refractory neuropathic
pain [61].
Recommendation: There is a weak recommendation for
the combination of antidepressants (SNRIs or TCAs) with
gabapentinoids or morphine and for the combination of
gabapentinoids and opioids in neuropathic pain, based
on evidence dating from before 2013 and the results of
two more recent high-quality trials. The evidence for
other combinations is inconclusive.
3.2.7. Cannabinoids
We identified nine placebo-controlled studies on cannabi-
noids (mostly transmucosal nabiximols and oral THC, only
two yielding positive results) published before June 2013, with
a moderate final quality of evidence against their use. We
identified two additional more recent high-quality RCTs of
cannabinoids in neuropathic pain: one study of nabiximols
(Sativex, 128 patients treated) yielded positive results for
peripheral neuropathic pain, albeit with a modest effect size
(NNT = 8.3); another study of oral dronabinol (tetrahydrocan-
nabinol or THC, 124 patients treated) yielded negative results
for neuropathic pain due to multiple sclerosis [62,63]. The final
quality of evidence was high.
Recommendation: The evidence concerning the level of
recommendation for the use of cannabinoids (transmu-
cosal nabiximols, oral THC) in neuropathic pain is incon-
clusive due to large number of high-quality trials yielding
negative results.
3.2.8. New drugs
One moderate-quality RCT compared cebranopadol, a
novel drug combining nociceptin/orphanin peptide and
opioid receptor agonism, to tapentadol and placebo in
chronic low back pain with a neuropathic component, and
reported similar efficacies in patients with and without
neuropathic pain components [43]. One study of the
alpha2delta ligand mirogabalin yielded positive results
for diabetic painful neuropathy [64]. One study reported a
significant effect of the NGF antagonist fulranumab in
diabetic painful neuropathy, whereas another reported
negative results for this drug in post-traumatic neuropa-
thic pain [65,66], but these studies were stopped pre-
maturely due to potential safety concerns with this drug
class (rapidly progressive osteoarthritis). One study of a
topical Nav1.7 antagonist in postherpetic neuralgia yielded
negative results, but this drug was found to be beneficial
in 63% of patients carrying a particular Nav1.7 polymor-
phism versus only 35% of patients without this variant
[67]. One study of an orally administered Nav1.7 antago-
nist in painful diabetic polyneuropathy reported negative
results overall, but positive results for patients with
‘‘burning pain’’ based on the NPSI [68]. Two phase II
studies of an angiotensin type II antagonist were stopped
prematurely in April 2019 due to safety issues in monkeys.
3.2.9. Lack of data
Based on our inclusion criteria, we were unable to obtain data
for the use of nefopam [69], paracetamol [70], NSAIDs [71] and
midazolam in neuropathic pain.
3.3. Oral ketamine, intravenous drugs, nerve blocks and
intrathecal therapy
3.3.1. Oral ketamine
We identified two double-blind studies of oral ketamine
published since 1966 (135 patients treated): one high-quality
placebo-controlled study in patients with cancer neuropathic
pain, which reported negative results for the primary outcome
[72], and one moderate-quality comparative study of oral
 revue neurologique 176 (2020) 325–352
methadone, ketamine and their combination in neuropathic
pain refractory to conventional therapy, which reported a
significant improvement in pain relative to baseline of similar
magnitude in all three groups [61]. However, in this second
study, only ketamine decreased allodynia and burning pain.
The final quality of evidence was low.
Recommendation: The evidence is inconclusive for the
use of oral ketamine in neuropathic pain.
3.3.2. Intravenous drugs
We identified three placebo-controlled studies of intravenous
(IV) lidocaine (70 patients treated) published since 1966. Two of
these trials used continuous lidocaine infusions (from 3 to
7.5 mg/kg) once weekly for four consecutive weeks, one in
diabetic neuropathic pain (low-quality trial) [73] and the other
in a mixed group (postherpetic neuralgia and CRPS; high-
quality trial) [74]. These trials yielded positive results at the
end of the fourth week, but this effect did not persist four
weeks later. However, the highest quality trial (very high) [75]
evaluating the efficacy of a single infusion (5 mg/kg) gave
negative results at week 4.
We identified only one placebo-controlled study assessing
the long-term efficacy of IV ketamine in neuropathic pain
published since 1966. In this single-center moderate-quality
study of 40 patients randomized to two groups, a five-hour
daily infusion of ketamine (80 mg/day) every day for one week
as an adjuvant to gabapentin was effective against spinal cord
injury pain one and two weeks after the last infusion, but
negative results were obtained at three weeks [76].
Overall, studies of iv lidocaine and ketamine generally
supported short-term efficacy for these drugs (i.e. one to three
weeks after the infusion) but a lack of long-term efficacy
(beyond three to four weeks), with a low-to-moderate final
quality of evidence. No data were found for other iv drugs,
including, in particular B12 injections [77].
Recommendation: The evidence concerning the level of
recommendation for iv lidocaine and ketamine in neu-
ropathic pain is inconclusive. However, given the poten-
tial short-term efficacy of these drugs after their infusion,
they might be useful for dealing with acute exacerbations
of neuropathic pain (low-quality of evidence).
3.3.3. Nerve blocks
We identified two high-quality studies fulfilling our inclusion
criteria published since 1966 (including 289 patients). Both
used a combination of lidocaine and methylprednisolone, but
they gave opposite results [78,79]. One gave negative results
for pudendal neuralgia, whereas the other gave positive
results for the treatment of pain due to various nerve injuries.
The final quality of evidence was moderate.
333
Recommendation: The evidence was inconclusive
concerning the level of recommendation for nerve blocks
in neuropathic pain.
3.3.4. Intrathecal therapy
We identified two double-blind placebo-controlled studies of
intrathecal (IT) methylprednisolone for neuropathic pain
performed on patients with intractable postherpetic neuralgia
(139 patients treated) since 1966. The first was initially
considered to be of high-quality [80], but was subsequently
downgraded to moderate quality as the results were incons-
istent with those of other studies of PHN and clinical
experience. This study has since been heavily criticized [14].
An independent group was unable to reproduce its results and
preclinical data are against IT corticosteroid efficacy [81,82]. In
the second study, IT methylprednisolone (60 mg), midazolam
(2 mg) and their combination were assessed in postherpetic
neuralgia involving lumbosacral dermatomes. The combina-
tion was superior to each of the drugs delivered as a
monotherapy [83]. The final quality of evidence was low to
moderate.
Recommendation: The evidence is inconclusive regard-
ing the level of recommendation for intrathecal therapy
with methylprednisolone for neuropathic pain. We
found no data for ziconotide, morphine and clonidine
in neuropathic pain, as no double-blind study specifically
assessing neuropathic pain has been published. This
does not rule out potential efficacy for IT morphine
and ziconotide, as these drugs have been shown to be
beneficial in double-blind trials in patients with refrac-
tory chronic pain, including patients with neuropathic
pain [84,85].
3.4. Neurostimulation therapy and invasive procedures
3.4.1. Peripheral noninvasive neurostimulation
We identified nine RCTs of transcutaneous electrical nerve
stimulation (TENS) published since 1966: one of high-quality,
six of moderate quality and two of low-quality (332 actively
treated patients) [86–94]. All but one of these studies assessed
peripheral neuropathic pain (the exception concerned spinal
cord injury pain) and were sham-controlled (six studies) or
had an active control group (three studies). One study had a
double-blind design and seven used a single-blind design
(three with patient blinding and four with investigator
blinding). Eight studies, including the double-blind study,
gave positive results for pain, albeit with a modest effect size.
One other low-quality RCT evaluated the impact of local
injections of cobalamine, lidocaine or both in addition to
TENS. TENS seemed to be more effective when combined with
334 revue neurologique 176 (2020) 325–352
local injections of cobalamine [95]. Tolerability was excellent,
with only minor skin irritations reported in some patients.
These studies were generally in favor of TENS as an effective
treatment for peripheral neuropathic pain, with a moderate
quality of evidence.
We identified one study of static magnetic field treatment
for painful diabetic neuropathy, which yielded positive results
for the primary outcome [96]. Two well-conducted double-
blind placebo-controlled studies of pulsed magnetic field
treatments in the same population gave negative results
[97,98]. Two double-blind studies conducted by the same
group investigated the impact of frequency-modulated elec-
tromagnetic neural stimulation (FREMS) for painful diabetic
neuropathy [99,100]. These FREMS studies included a total of
85 actively treated patients, and the largest study yielded
negative results. These studies generally supported a lack of
efficacy of pulsed magnetic field and FREMS treatments, with a
low final quality of evidence.
Recommendation: There is a weak recommendation for
the use of TENS in peripheral neuropathic pain (moderate
final quality of evidence). There is a weak recommenda-
tion against the use of static or pulsed magnetic fields
(low final quality).
3.4.2. Central noninvasive neurostimulation
We identified 16 placebo-controlled studies of central non-
invasive neurostimulation in various neuropathic pain condi-
tions. Seven studies of low-to-moderate quality used
repetitive transcranial magnetic stimulation (rTMS) of the
primary motor cortex (M1) on a total of 121 actively stimulated
patients [101–107]. Protocols were heterogeneous in terms of
the stimulation frequency used (5 to 20 Hz), number of pulses
per session (500 to 2000), and number of sessions (5 or 10). One
study involving a small number of pulses (500) showed pain
reduction only immediately after stimulation [103], whereas
all the others reported prolonged analgesia, for at least 15 days
after the end of sessions, and for at least seven weeks in four
studies [101,102,105,107]. These studies generally supported
the efficacy of high-frequency rTMS of the motor cortex for the
treatment of neuropathic pain, with a moderate final quality of
evidence. One small study in which the novel Hesed coil
(‘‘deep rTMS’’) device was used in 25 patients yielded positive
results [108]. Two studies targeting the left dorsolateral
prefrontal cortex (DLPF) (n = 21) [109] or the posterior insula
and anterior cingulate cortex (n = 98) [110] gave negative
results (moderate final quality of evidence).
Three low- to moderate-quality studies used transcranial
direct current stimulation (tDCS) with anodal M1 montage in a
total of 46 actively stimulated patients [111–113]. One study
showed analgesia for four weeks after five daily sessions,
whereas the other two yielded negative results. These studies
were generally supported a lack of efficacy of tDCS, but the
final quality of evidence was low. One small, low-quality study
of transcutaneous spinal direct current stimulation (tsDCS) in
neuropathic pain due to multiple sclerosis gave positive
results [114].
Cranial electrotherapy stimulation (CES) involves the
application of a small amount of current through the head
via ear-clip electrodes. Two studies conducted by the same
group investigated the effect of CES in a total of 67 stimulated
patients with spinal cord injury [115,116]. Both yielded positive
results for pain, but with a small effect size. The final quality of
evidence was low.
Recommendation: There is a weak recommendation for
the use of high-frequency rTMS of the motor cortex in
neuropathic pain (moderate final quality of evidence).
The evidence concerning the level of recommendation of
rTMS for DLPFC, tDCS, tsDCS and CES is inconclusive
(low-quality of evidence), and there is a weak recommen-
dation against the use of rTMS of the posterior insula and
anterior cingulate cortex in neuropathic pain (one high-
quality study with negative results).
3.4.3. Pulsed radiofrequency (PRF)
PRF works by delivering a targeted electrical field to the
dorsal root ganglion (DRG) via a catheter needle tip, without
causing damage, as the temperature is maintained at or
below 42 8C [117]. By contrast, conventional radiofrequency
thermocoagulation exposes the target nerves to continuous
electrical stimulation and produces a lesion by increasing
the temperature around the tip of the needle. We identified
12 double-blind studies of PRF for radicular pain or post-
herpetic neuralgia (PHN) in 383 actively treated patients
[118–129]. Six of these studies were of high-quality, with four
yielding positive results [119,121,123,129]. One of these
studies with positive results concerned cervical radicular
pain, one concerned lumbosacral radicular pain and the
other two related to thoracic PHN. The two high-quality
studies yielding negative results for pain concerned lumbo-
sacral radicular pain [118,122]. The six lower quality studies
either gave positive results for pain or reported non-
inferiority relative to the comparative group (conventional
radiofrequency in one case and percutaneous nucleoplasty
in the other). No major adverse effects were reported. These
studies were in favor of pulsed radiofrequency as an
effective treatment for thoracic PHN, with a moderate
quality of evidence.
Recommendation: There is a weak recommendation for
the use of pulsed radiofrequency in thoracic postherpetic
neuralgia (moderate final quality of evidence). The data
are inconclusive for radicular pain (two studies yielding
positive results and two yielding negative results, all of
high-quality).
 revue neurologique 176 (2020) 325–352
3.4.4. Peripheral invasive nerve stimulation
We identified two sham-controlled single-blind studies of
percutaneous electrical nerve stimulation (PENS) applied for
three consecutive weeks (30 minutes, 3 times a week), to treat
peripheral neuropathic pain due to sciatica or diabetic
neuropathy, yielding positive results for pain intensity
[88,130]. In one study, PENS was also significantly more
effective than TENS for improving sleep and function. The
quality of evidence was considered low, as both studies were
single-blind and performed by the same group. One low-
quality study of implanted peripheral nerve stimulation in 45
actively treated patients yielded positive results [131]. One
moderate-quality open-label trial compared SCS and dorsal
root ganglion (DRG) stimulation [132]. A subgroup analysis of
patients with neuropathic pain and peripheral nerve lesions
suggested that both techniques were effective, with DRG
stimulation at least non-inferior to SCS.
Recommendation: The evidence concerning the level of
recommendation for peripheral invasive nerve stimula-
tion, including DRG stimulation for the treatment of
neuropathic pain is inconclusive.
3.4.5. Central invasive neurostimulation
We identified seven moderate-quality open-label controlled
studies [133–138] and one high-quality double-blind RCT
[139] of spinal cord stimulation (SCS) using conventional or
recently developed stimulation paradigms for failed back
surgery syndrome or diabetic painful neuropathy. Four
studies of conventional SCS for failed back surgery syndrome
or diabetic painful neuropathy, involving a total of 144
patients with SCS [133–136], gave positive results with a large
effect size (NNT of 1.7 to 2.8): these studies compared SCS to
repeated lumbosacral spine surgery in one study [133] and
conventional medical management in the other three
studies. Two subsequent open-label RCTs involving 297
patients stimulated with recently developed paradigms
(paresthesia-free, high-frequency stimulation at 10 kHz)
reported high levels of efficacy relative to conventional
parameters (usually around 80 Hz) for failed back surgery
syndromes or back and leg pain [137,138]. One moderate-
quality open-label trial compared SCS and dorsal root
ganglion (DRG) stimulation [132]. A subgroup analysis of
patients with neuropathic pain and peripheral nerve lesions
suggested that both techniques were effective, with DRG
stimulation at least non-inferior to SCS. One small double-
blind study of 24 patients with failed back surgery syndrome
found a significant effect of very high-frequency stimulation
(5882 Hz) versus sham stimulation, whereas stimulation at
lower frequencies (1200 Hz and 3030 Hz) was no more
effective than sham stimulation [139]. The most frequent
complications were related to hardware dysfunction (e.g.
migration, disconnection, electrode breakage) potentially
requiring additional surgery for up to 24% of patients in one
study conducted 15 years ago [134], but only 4% in the largest
335
study, which included 198 patients and was performed much
more recently [137]. In this last study, the most frequent
adverse event was implant site pain, which affected 11% of
patients, and no SCS-related serious adverse events were
reported. The risk of spinal cord damage, through direct
lesions or indirect compression by epidural hematoma, is
exceptionally low. The final quality of evidence was
moderate.
Based on our inclusion criteria (including at least three
weeks of follow-up in a controlled clinical trial), we identified
only one RCT of invasive epidural motor cortex stimulation
(EMCS) with double-blind assessment over one month,
involving a comparison of the ON and OFF conditions, in a
total of 13 patients [140]. The pain rating index of the McGill
Pain Questionnaire (secondary endpoint) was significantly
lower in the ON than in the OFF condition, but no effect on pain
intensity (primary endpoint) was observed. The quality of
evidence was low. By contrast, previous uncontrolled open-
label studies had suggested that EMCS (frequency 20–65 Hz,
amplitude 1–6 V, pulse width 60–450 ms) might be beneficial,
particularly in patients undergoing several sessions of high-
frequency rTMS of the motor cortex.
We identified no studies meeting our inclusion criteria and
providing data concerning the efficacy of deep brain stimula-
tion in neuropathic pain.
Recommendation: All the controlled studies of conven-
tional SCS in failed back surgery syndrome and diabetic
neuropathic pain yielded positive results, with large
effect sizes and a low risk of adverse effects, but these
studies were open-label and generally compared SCS to
standard care. This resulted in a weak GRADE recom-
mendation for the use of conventional SCS in neuropath-
ic pain associated with failed back surgery syndrome and
diabetic painful neuropathies (moderate final quality of
evidence). The evidence concerning the level of recom-
mendation for invasive motor cortex stimulation in neu-
ropathic pain is inconclusive (low-quality of evidence).
3.4.6. Other surgical interventions
We identified four controlled open-label studies of various
surgical interventions for neuropathic pain [141–144]. There
was only one high-quality study, which concerned percuta-
neous epidural adhesiolysis in chronic lumbar radicular pain
and yielded positive results [142]. The other three studies
were of low-to-moderate quality and evaluated long-wave
diathermy and interferential currents in chemotherapy-
induced neuropathy (negative), nerve decompression in
painful diabetic neuropathy (positive), and decompression
and transposition of the pudendal nerve in pudendal
neuralgia (positive). The final quality of evidence was low
to moderate.
No eligible study concerning the microsurgical approach to
the dorsal root entry zone (DREZotomy) was identified.
336 revue neurologique 176 (2020) 325–352
Recommendation: The evidence was inconclusive
concerning the level of recommendation for epidural
adhesiolysis, long-wave diathermy and nerve decom-
pression in neuropathic pain. There were no data
concerning DREZotomy. This does not rule out its poten-
tial efficacy in spinal nerve root pain (brachial plexus
avulsion or cauda equina injury), as reported in uncon-
trolled open-label studies [145,146].
3.5. Psychotherapy
We identified five open-label RCTs of psychotherapy for
neuropathic pain: three concerned cognitive behavioral the-
rapy (CBT) in a total of 89 patients [147–149] and two related to
mindfulness in 46 patients [150,151]. One study used supportive
psychotherapy as a control group [147], whereas the other four
used usual care alone (waiting list). Two low-quality CBT
studies on group therapy for neuropathic pain related to HIV
[147] or spinal cord injury [148] reported positive effects on pain
intensity. The third moderate-quality study [149] of a web-
based CBT intervention (10 modules, including videos, exercise
sheets to be downloaded, navigation on the dedicated website,
available only to study participants) reported a decrease in pain
intensity in chemotherapy-induced painful neuropathies. This
study also suggested that web-based interventions are feasible
in this context. Two RCTs assessed the efficacy of mindfulness
versus usual care in patients with neuropathic pain. The first of
these studies was a low-quality pilot study of individual daily
meditation sessions for six weeks; it reported negative results
for pain intensity in elderly patients with postherpetic
neuralgia [150]. By contrast, the second study was a high-
quality study of group therapy as part of a mindfulness-based
stress reduction program (MBSR) in patients with painful
diabetic neuropathy; it demonstrated clear efficacy, with a
large effect (NNT = 2.4) [151]. Both studies reported an effect of
mindfulness on quality of life, function and catastrophizing.
The final quality of evidence was moderate.
Recommendation: There is a weak recommendation for
the use of cognitive behavior therapy and mindfulness as
an add-on therapy for neuropathic pain (moderate final
quality of evidence).
3.6. Other miscellaneous non-drug treatments
Seven studies using various nondrug treatments were identi-
fied. One low-quality study compared aromatherapy massage
to usual care alone and suggested a small improvement of pain
and quality of life [152]. One moderate-quality study of auricular
acupuncture for SCI pain reported positive results [153]. One
low-quality study investigated the impact of low-level laser
treatment for postherpetic neuralgia and reported positive
results relative to the placebo [154]. One moderate-quality study
of vitamin E supplementation in patients with diabetic painful
neuropathy reported negative results [155], as did a high-quality
study in the same population [156]. One low-quality study
reported a small non-significant benefit of exercise versus
education for peripheral neuropathic pain [157].
Based on our inclusion criteria, we identified no eligible
studies concerning the use of mirror therapy, musicotherapy,
art therapy, hypnotherapy, physiotherapy, mesotherapy,
homeopathy, therapeutic patient education, tai chi or Chinese
acupuncture.
Recommendation: The evidence concerning the level of
recommendation for aromatherapy, auricular acupunc-
ture and low-level laser therapy was inconclusive, as it
was obtained in single low- or moderate-quality trials,
and there is a weak recommendation against the use of
vitamin E in neuropathic pain. There were no data
concerning other complementary therapies. This does
not rule out the potential efficacy of mirror therapy,
hypnosis and acupuncture in neuropathic pain, which
have been evaluated in randomized controlled studies in
which neuropathic pain was assessed at early time
points (before 3 weeks) or in trials not focusing on neu-
ropathic pain [158–160].
3.7. Studies in pediatric or elderly populations
Only one small comparative study was identified in children
[161]. It showed that both 10 mg/day amitriptyline and 900 mg/
day gabapentin decreased pain relative to baseline. There was
no significant difference between treatments and no major side
effects. We identified only one specific study in elderly patients
(mean age: 72 years) focusing on mindfulness (see above).
3.8. Therapeutic algorithm in adults
Details regarding the GRADE recommendations are provided
in Tables 1–3 and Fig. 2. Table 4 presents practical recom-
mendation for use. All the proposals were deemed appropriate
by the reading group (median  7). Relative (range: 5 to 9) or
strong (range: 7 to 9) agreement of at least 90% of reading group
members [162] was obtained for all recommendations except
the one for carbamazepine (Appendix 6).
4. Discussion
This manuscript presents French recommendations for the
treatment of neuropathic pain based on a comprehensive
systematic review of pharmacological and non-pharmacolo-
gical therapies. Given the heterogeneous nature of the
treatments and designs considered here, we did not conduct
a new meta-analysis and do not, therefore, report the effect
sizes or number needed to treat (NNT) for a group of therapies.
However, we have provided these quantitative data, when
available, for individual studies (see Appendix 5). We used the
 revue neurologique 176 (2020) 325–352 337

Table 1 – Guidelines for pharmacotherapy (available in France) based on grade.

Grade Drugs Daily dosages/regimenRecommendations Specific safety issues (warning)
Strong for Duloxetine 60–120 mg/day First line Contraindicated with monoamine
oxidase inhibitors, and in cases of hepatic
or severe renal failure. Suicidal behavior
(low risk), due to disinhibiting effects
Venlafaxine 150–225 mg/day First line
Gabapentin 1200–3600 mg/day First line Potential abuse
TCAs 25–150 mg/day First line (2nd line in the elderly) Contraindicated with monoamine
oxidase inhibitors, and in cases of closed-
angle glaucoma risk, urinary retention
risk or recent myocardial infarction.
Suicidal behavior (low risk) due to
disinhibiting effect
Weak for Lidocaine plasters 1–3 plasters for 12 h/day First line for peripheral NP Contraindicated on broken skin
Pregabalin 150–600 mg/day Second line (alternative to Potential abuse
gabapentin)
Capsaicin 8% 1–4 patches/3 months Second line for peripheral NP Available in a limited number of pain
units
BTX-A (SC) 50–300 U/3 months Second line for NP Available in a limited number of pain
units
Combination TCA (or SNRIs) + opioids Second or third line (if opioids) Greater risk for combinations of
or + gabapentinoids gabapentinoids with opioids (even
tramadol)
Tramadol 100–400 mg/day Second line Potential abuse. Contraindicated with
monoamine oxidase inhibitors, and in
cases of severe respiratory failure
Strong opioids < 150 MME/day Third line (in absence of Potential abuse. Greater risk when
alternative) combined with gabapentinoids
Inconclusive Capsaicin cream
Carbamazepine
Clonidine topical
Lacosamidea
Oxcarbazepineb
IV ketamine
IV lidocainec
Lamotrigine
SSRIs
Topiramate
Zonisamide
Cannabinoids
Weak against Valproate
Strong against Levetiracetam
Mexiletine
Lack of data for Nefopam paracetamol
neuropathic NSAIDs clonazepam
pain Midazolam
Vitamin B12
Only treatments available in France are included in this table.
What does GRADE recommendation mean?: Strong for: high-quality evidence that the desirable effects of the intervention are clearly greater
than its undesirable effects. Weak for or weak against: uncertainty about the trade-offs (because of low- to moderate-quality evidence or
because the desirable and undesirable effects balance out). Generally inconclusive: not enough data to conclude for neuropathic pain in
general. This does not mean that these treatments are or are not effective, and they can be proposed in specific situations. Strong against:
high-quality evidence that the desirable effects are clearly not greater than the undesirable effects. Lack of data: absence of studies
corresponding to the inclusion criteria. This does not mean that the treatments are effective or ineffective.
TCAs: tricyclic antidepressants; BTX: botulinum toxin; MME: morphine milligram equivalent; TCA: tricyclic antidepressant; SSRIs: selective
serotonin reuptake inhibitors; BID: bis in die (= twice daily); NSAIDs: nonsteroidal anti-inflammatory drugs; GRADE: grading of
recommendations assessment, development and evaluation.
a
Could be of interest in a specific population of patients with Nav1.7 mutation-related small-fiber neuropathy (based on a single study).
b
Could be of interest in patients with peripheral neuropathy and ‘‘irritable nociceptor’’ phenotype (i.e., limited thermal deficit) (based on a
single study).
c
IV ketamine (0.25 to 1 mg/kg per day) and IV lidocaine (3–7.5 mg/kg, once weekly) may be proposed to overcome acute pain exacerbations in
patients with neuropathic pain refractory to more conventional medication, because of their short-lasting analgesic effects (less than 4 weeks
in double-blind trials using these doses and modes of administration). Careful cardiac monitoring is warranted with lidocaine. Misuse and
long-term side effects (particularly renal and hepatic toxicity) should be monitored in cases of repeated ketamine infusions.
338 revue neurologique 176 (2020) 325–352

Table 2 – Intrathecal therapy, neurostimulation and surgery.

Grade Treatment Regimen Recommendations Specific safety issues
(warning)
Weak for TENS  30 min/day First line Seizures (HF-rTMS)
HF-rTMS over M1 > 1200 pulses/session, > 5 Hz Third line
Pulsed radiofrequency Paresthesia elicited along the Thoracic post-herpetic
tested nerve root at low intensities; neuralgia
PRF settings 42 8C, 120 seconds/
twice for the same level
Spinal cord stimulation Conventional (40 to 80 Hz) or high- Third line (FBSS or diabetic
frequency stimulation (without polyneuropathy)
paresthesia, 1 to 10 kHz)
Inconclusive Intrathecal
methylprednisolone
Anodal M1 tDCS
CES
PENS
EMCS
HF-rTMS over DLPFC
Weak against HF-rTMS over posterior
insula or ACC
Pulsed magnetic field
FREMS
Lack of data for Intrathecal morphine,
neuropathic pain ziconotide or clonidine
DBS
TENS: transcutaneous electrical nerve stimulation; HF-rTMS: high-frequency repetitive transcranial magnetic stimulation; M1: primary motor
cortex; IT: intrathecal; IV: intravenous; FBSS: failed back surgery syndrome; tDCS: transcutaneous direct current stimulation; PENS:
percutaneous electrical nerve stimulation; EMCS: epidural motor cortex stimulation; DBS: deep brain stimulation; DLPFC: dorsolateral
prefrontal cortex; ACC: anterior cingulate cortex; FREMS: frequency-modulated electromagnetic neural stimulation; CES: cranial electro-
therapy stimulation.
What does GRADE recommendation mean?: Strong for: high-quality evidence that the desirable effects of the intervention are clearly greater
than its undesirable effects. Weak for or weak against: uncertainty about the trade-offs (because of low- to moderate-quality evidence or
because the desirable and undesirable effects balance out). Generally inconclusive: not enough data to conclude for neuropathic pain in
general. This does not mean that these treatments are or are not effective, and they can be proposed in specific situations. Strong against:
high-quality evidence that the desirable effects are clearly not greater than the undesirable effects. Lack of data: absence of studies
corresponding to the inclusion criteria. This does not mean that the treatments are effective or ineffective.

Table 3 – Psychotherapies and complementary therapies.

Grade Treatment Regimen Recommendations Specific safety issues (warning)
Weak for Cognitive behavioral therapy As an adjuvant treatment
Mindfulness-based stress reduction
Weak against Vitamin E
Lack of data for Other psychotherapies
neuropathic pain Massage
Aromatherapy
Auriculotherapy
Musicotherapy
Art therapy
Hypnotherapya
Physiotherapy
Mesotherapy
Mirror therapya
Homeopathy
Tai chi
Chinese acupuncturea
What does GRADE recommendation mean?: Strong for: high-quality evidence that the desirable effects of the intervention are clearly greater
than its undesirable effects. Weak for or weak against: uncertainty about the trade-offs (because of low- to moderate-quality evidence or
because the desirable and undesirable effects balance out). Generally inconclusive: not enough data to conclude for neuropathic pain in
general. This does not mean that these treatments are or are not effective, and they can be proposed in specific situations. Strong against:
high-quality evidence that the desirable effects are clearly not greater than the undesirable effects. Lack of data: absence of studies
corresponding to the inclusion criteria. This does not mean that the treatments are effective or ineffective.
a
See Table 4 for additional information regarding these treatments.
 revue neurologique 176 (2020) 325–352 339

Fig. 2 – Proposed therapeutic algorithm for neuropathic pain treatment in adults. Only treatments available in France in June
2019 were considered. For practical considerations, see Table 4. NP: neuropathic pain; TCAs: tricyclic antidepressants;
TENS: transcutaneous electrical nerve stimulation; HF-rTMS: high-frequency repetitive transcranial magnetic stimulation;
M1: primary motor cortex; BTX-A: botulinum toxin type A; FBSS: failed back surgery syndrome; MME: mg morphine
equivalent.

GRADE system to assess the quality of evidence for all
treatments, and our recommendations comply with the
AGREE II guidelines [20,163]. The GRADE system makes it
possible to combine studies of heterogeneous quality, because
it allows the upgrading of controlled open-label studies with a
high final quality and the downgrading of double-blind studies
with many biases [163].
The major strength of this systematic review is that it is the
first based on a comprehensive assessment of all therapies
proposed for neuropathic pain treatment, encompassing
pharmacological treatments and all other types of other
medical/surgical treatment. All previous international recom-
mendations for neuropathic pain focused on a specific
treatment, such as pharmacotherapy [13], neurostimulation
[15] or invasive therapy [14]. We also propose evidence-based
recommendations for psychotherapies and complementary
medicine.
Our therapeutic algorithm for pharmacotherapy is driven
by the drug treatment rather than by the etiology or
peripheral/central lesion responsible for pain, as in the 2015
NeuPSIG recommendations [13] and previous French recom-
mendations [12]. Indeed, neuropathic pain is now fully
recognized to have multiple etiologies across similar neuropa-
thic syndromes [164,165]. In previous French recommenda-
tions [12] based on a systematic review, TCAs, gabapentin and
pregabalin were proposed as first-line treatments, duloxetine
and lidocaine patches as second-line treatments and strong
opioids as third-line treatments. The most recent meta-
analysis and systematic study of pharmacotherapy establis-
hed the efficacy of TCAs, SNRIs, gabapentin, pregabalin,
tramadol and strong opioids for neuropathic pain, and that of
topical agents (topical lidocaine, high-concentration capsaicin
and botulinum toxin A) for peripheral neuropathic pain [13].
This analysis provided strong GRADE recommendations for
the use of antidepressants, pregabalin and gabapentin, which
were proposed as first-line treatments, and a weak GRADE
recommendation for topical agents and opioids, which were
proposed as second-line (for topical agents and tramadol) or
third-line (for strong opioids and botulinum toxin A) treat-
ments, but they did not recommend combination therapy
because few high-quality studies were available at the time
[13]. Since the completion of this previous systematic study,
we have identified 22 studies of monotherapy with TCAs,
duloxetine, gabapentin, lidocaine plasters or botulinum toxin
A providing positive results for neuropathic pain and which
were generally of high-quality, and one moderate-quality
study of high-concentration capsaicin patches that also
yielded positive results. No new studies of venlafaxine were
identified. Hence, the level of recommendation based on
GRADE remains strong for tricyclic antidepressants (at
340
Table 4 – Practical use of treatments for chronic neuropathic pain available in France.
First line for focal peripheral
neuropathic pain
First line for any neuropathic pain
Second line for focal peripheral
neuropathic pain
Second line for any neuropathic
pain
revue neurologique 176 (2020) 325–352
First-line treatments for focal peripheral neuropathic pain include: lidocaine plasters, 1
to 3 plasters depending on the extent of pain, 12 hours per day. Adverse effects mostly
skin irritation or allergy; ttranscutaneous electrical pain stimulation. Reimbursed if
prescribed by specialist pain units in France. Adverse effects mostly skin irritation or
allergy
These topical therapies may be used as standalone treatments or in combination with
systemic drugs (expert consensus) and should be preferred in patients with limited area
of pain and residual sensitivity (i.e. lack of total anesthesia to thermal or mechanical
stimulation of the painful area)
First-line treatments for any neuropathic pain include: oral SNRIs: duloxetine (60–
120 mg per day once daily or BID) or venlafaxine (150–225 mg daily administered BID or
TID) with a preference for duloxetine (based on higher quality trials with positive
results). Main adverse effects include nausea, decreased appetite, constipation and
sexual side effects. Rare cases of high blood pressure have been reported with high
doses of venlafaxine ( 150 mg daily). Suicidal ideation is rare, but possible on initiation
of any antidepressants (warning); oral gabapentin (1200–3600 mg administered TID).
Main adverse effects include drowsiness, dizziness, weight gain and peripheral edema.
Misuse risk factors should be investigated before prescription of gabapentin and
potential misuse or abuse should be assessed at each renewal because of the potential
for the misuse of this drug; oral TCAs (i.e., amitriptyline, clomipramine, imipramine),
10–150 mg per day administered once daily or BID. Low doses (< 75 mg/d) are usually
effective. Common adverse effects include drowsiness and weight gain. Suicidal
ideation is rare, but possible at initiation of any antidepressant (warning). TCAs should
be carefully monitored for cardiac effects, anticholinergic effects or postural
hypotension, especially in polymedicated patients, patients with multiple diseases and
at doses > 75 mg daily. In the elderly, polymedicated adults or adults with multiple
diseases, doses should not exceed 75 mg per day
The ‘‘start low and go slow’’ approach is essential for all orally administered drugs, to
minimize adverse effects and patients should be advised of the risk of an impairment of
their ability to drive, particularly at treatment initiation
Second-line treatments for focal peripheral neuropathic pain include: capsaicin, high-
concentration patches (1 to 4 patches depending on the extent of pain, applied for
30 minutes on the feet or 60 minutes for other body areas). Main adverse effects include
acute burning pain after application (which may be reduced by cold applications),
redness and swelling. Rare cases of high blood pressure have been reported because of
the acute pain induced by application. Patients should therefore be monitored for acute
pain and blood pressure for at least one hour after application; botulinum toxin A (up to
300 units subcutaneously into the painful area, depending on the extent of the pain).
Adverse effects consist principally of pain due to the injection
These drugs are available for hospital use only (and at the day hospital for capsaicin).
They may be used as standalone treatments or combined with systemic drugs (expert
consensus) and should be preferred in patients with a limited area of pain, residual
sensitivity (i.e. lack of total anesthesia to thermal or mechanical stimulation of the
painful area), and mechanical allodynia for botulinum toxin A. Botulinum toxin A can
be prescribed only by specialists
Second-line treatments for any neuropathic pain include: oral pregabalin (150–600 mg
daily, administered BID or TID as an alternative to gabapentin in cases of poor
tolerability or inefficacy). Main adverse effects include drowsiness, dizziness, weight
gain and peripheral edema. Misuse risk factors should be investigated before
prescription and potential misuse or abuse should be assessed at each renewal because
of the potential for abuse (apparently more commonly than with gabapentin);
sustained-release oral tramadol (100–400 mg daily BID or once daily; a single once daily
preparation is available for use). Tramadol has the same side effects and potential abuse
risks as strong opioids (see below), although such risks are less common, as the
maximum dose of tramadol (400 mg/day), corresponds to 40 to 68 mg morphine
equivalent (evidence.nhs.uk). Tramadol may be combined with antiepileptics (expert
consensus), but should be used with caution with high-dose antidepressants (potential
risk of serotoninergic syndrome); combination of antidepressants (TCAs 25–75 mg daily
or duloxetine 60 mg daily) with gabapentinoids (pregabalin 150–300 mg daily or
gabapentin 1200–1800 mg daily); cognitive behavioral therapy and mindfulness. These
techniques have the highest level of evidence amongst psychotherapies and are
recommended as add-ons to other therapies (as controlled studies showing their
efficacy were conducted in patients receiving pharmacotherapy)
The ‘‘start low and go slow’’ approach is essential for all orally administered drugs, to
minimize adverse effects, and patients should be advised of the risk of an impairment
of their ability to drive, particularly at treatment initiation
 revue neurologique 176 (2020) 325–352 341

Third line Third-line treatments for neuropathic pain include: high-frequency rTMS of the motor
cortex (80% of the motor threshold, 10 Hz, 1500 to 3000 pulses per session) can be
proposed for localized or more diffuse pain (i.e. spinal cord injury or diabetic painful
neuropathy). This technique is available only at specialized centers. The principal
adverse effects are headache within hours of the session. Seizures are exceptional
(warning); spinal cord stimulation (SCS) has been found to be effective in failed back
surgery syndrome and painful diabetic polyneuropathy. It is available only at
specialized centers. It may be considered before initiating strong opioids and after as
little as one year of pain. Like other invasive techniques, SCS should always be preceded
by careful psychological assessment of the patient. Complications are rare and are
mostly related to hardware dysfunction (e.g. migration, disconnection, electrode
breakage) potentially requiring additional surgery. The risk of spinal cord damage, due
to a direct lesion or indirect compression by epidural hematoma, is exceptionally low;
strong opioids, i.e. sustained-release oral morphine and oxycodone. Strong opioids
should be proposed in the absence of alternatives. They require careful evaluation of
potential risks of abuse, preferably with specific questionnaires, such as the opioid risk
tool, and should be used for the shortest possible duration (i.e. a few months), with
careful monitoring, and, preferably, with initiation by pain specialists. Their doses
should be titrated up slowly and should not exceed 150 mg morphine equivalent (expert
consensus). Immediate-release opioids should be avoided, particularly transmucosal
fentanyl (except in cases of associated cancer based on official approval for use) because
of the higher risk of abuse associated with these preparations. In the lack of substantial
improvements in pain, function or quality of life, opioids should be titrated down and
stopped. The main adverse effects include constipation, drowsiness, nausea, pruritus,
dysuria. Long-term opioid use is also associated with misuse, abuse, hypogonadism and
hypocortisolism [213]. Misuse risk factors should be investigated before prescription
and misuse or abuse should be assessed at each renewal. Opioid prescription should be
monitored particularly carefully in men under the age of 50 years, due to the endocrine
and misuse risks; combination of opioids with antidepressants or gabapentinoids, in
the absence of alternatives. Opioid doses (including tramadol) should be reduced in
combination with gabapentinoids due to recent reports of a greater risk of death with
such combinations [169]
Practical recommendations for No study has defined the rules for switching to second- or third-line therapy in
switch in treatment neuropathic pain. In the absence of contraindication, first-line treatments should be
tested first. In cases of intolerable adverse effects or treatment failure, defined as a
decrease in pain of less than 30% [214] and/or an improvement in function of less than
30% after a trial for at least six weeks at the maximum tolerated dose, a switch to
second-line therapy should be proposed (expert consensus). The same rules should
apply when switching from second- to third-line therapies (expert consensus)
TENS: transcutaneous electrical nerve stimulation; TCAs: tricyclic antidepressants; BID: bis in die (= twice daily); TID: ter in die (three times
daily); BTX-A: botulinum toxin type A; rTMS: repetitive transcranial magnetic stimulation; SCS: spinal cord stimulation; EMCS: epidural motor
cortex stimulation.

relevance of combining gabapentin with morphine for the

moderate doses), gabapentin and SNRIs, which we recom-
mend as first-line treatments, and weak for capsaicin patches,
which we recommend as a second-line treatment for peri-
pheral neuropathic pain and localized pain (Fig. 2). Based on
new high-quality studies reporting positive results for BTX-A
and on a good efficacy/safety ratio for both treatments
[166,167], we increased the GRADE level of recommendation
for topical lidocaine and botulinum toxin A, which we now
recommend as first- and second-line treatments, respectively,
for peripheral neuropathic pain in which the pain is confined
to a limited area. Based on recent high-quality combination
studies showing that combinations of TCAs with opioids or
with gabapentinoids are superior to monotherapy with these
agents, we now also recommend combinations of anti-
depressants and gabapentinoids as a second-line treatment
if insufficient pain relief is achieved with monotherapy. This
recommendation extends to the combination of SNRI anti-
depressants with pregabalin, based on one large-scale high-
quality trial giving positive results before the start date for our
search [168]. Again, based on one high-quality study dating
from before the start of our search and demonstrating the
treatment of neuropathic pain, we recommend this combina-
tion as a third-line treatment, in the absence of suitable
alternatives, with the proviso that it should be carefully
monitored, with prescription of the lowest possible doses, as
suggested by a well-conducted epidemiological retrospective
study reporting a higher risk of opioid-related death in patients
taking such a combination [169]. Low dose combination can be
effective and better tolerated than high dose monotherapy. No
more recent studies on tramadol were identified. The level of
recommendation for tramadol therefore remains unchanged
relative to the previous guidelines [13].
Contrary to all previous recommendations, we now
propose pregabalin as an alternative to gabapentin for
second-line treatment. Indeed, most recent large-scale high-
quality studies have shown pregabalin to be ineffective or only
weakly effective relative to placebo at doses similar to those
used in routine clinical practice (generally 300 mg daily). All
these studies, including those in which positive results were
obtained, had very small effect sizes. A recent high-quality
comparative study in chronic sciatica showed that gabapentin
was significantly more effective and had fewer adverse effects
342 revue neurologique 176 (2020) 325–352
than pregabalin [36]. This is also consistent with recent meta-
analyses reporting a lower number needed to harm (NNH) for
pregabalin (13.9) than for gabapentin (25.6) [13]. Another high-
quality study reported that pregabalin lacked efficacy against
acute and chronic sciatica [170]. Finally, the COMBO trial
comparing the efficacy of monotherapy with pregabalin or
duloxetine to the combination of these two drugs in diabetic
painful neuropathy also reported a significantly lower efficacy
for pregabalin (300 mg daily) than for duloxetine (60 mg daily)
in the first phase of the trial [168]. Overall, these data suggest
that the efficacy and safety of pregabalin was overestimated in
initial studies. Furthermore, recent evidence has revealed a
potential for abuse for drugs of this class [171–173]. Abuse is
increasingly reported for gabapentinoids and abuse rates
seem to be higher for pregabalin than for gabapentin [174–176].
We therefore recommend a careful monitoring of gabapenti-
noids. Prescribers should also be aware of high-risk popula-
tions (i.e. younger patients, patients with a history of
substance abuse, particularly opioids, and psychiatric comor-
bidities) and should monitor for signs of abuse, as for opioids
[177]. Of note, in the UK, gabapentinoids have been reclassified
as a class C-controlled drug since April 2019.</span></span>
Our recommendations regarding opioids should be seen in
the context of the dramatic opioid crisis in the USA, where
misuse rates and opioid-related mortality are high [178,179].
Indeed, prescription opioids were responsible for more than
17,000 deaths in the USA in 2017 (drugabuse.gov). The
situation is much less severe in France, but opioid prescription
rates are increasing [178,180], and guidelines should be
followed to limit the risk of misuse [177]. The evidence for
opioid efficacy and safety in neuropathic pain is stronger than
for other chronic pain syndromes, such as osteoarthritis and
back pain [177]. However, recent studies of strong opioids in
neuropathic pain were limited to fentanyl and transdermal
buprenorphine, and their results were inconclusive, contrast-
ing with the positive results obtained for oral morphine and
oxycodone in previous meta-analyses and systematic reviews
[12,13,177]. We therefore recommend oral sustained-release
morphine or oxycodone as a third-line treatment for neuropa-
thic pain, in the absence of suitable alternatives, with specific
warnings and careful monitoring (expert consensus). Opioids
should be prescribed for the shortest possible duration and
withdrawal anticipated (see Table 4 for practical use).
Tapentadol, a newer agent combining opioid agonism and
norepinephrine reuptake properties, is probably effective
against peripheral neuropathic pain, according to the results
of recent studies, but is not yet available in France.
Cannabinoids are under investigation for use against
refractory neuropathic pain in France at specialized pain
centers [181]. The previous recommendations [13] were
‘‘weakly against’’ their use, because of potential risks of abuse
and the larger number of trials giving negative than positive
results. Based on two recent trials, one reporting weakly
positive findings for nabiximols and with the other negative
results for dronabinol, the evidence was considered incon-
clusive, because there are still more studies giving negative
than positive results, for both compounds. This does not
exclude the possibility that cannabinoids act in subgroups of
patients or on specific symptoms, particularly paroxysmal
pain. The level of recommendation regarding other drug
treatments considered inconclusive or ‘‘weak against’’ in prior
meta-analyses generally remained similar in this analysis, in
the absence of new evidence for efficacy or safety.
We also considered clinical trials performed specifically in
children or in elderly or frail patients with neuropathic pain.
However, we were unable to find any high-quality studies
complying with our criteria. Our guidelines for these popu-
lations are, therefore, mostly based on expert consensus.
Thus, we recommend gabapentin (10 to 30 mg/kg per day, TID)
or amitriptyline (0.3 to 1 mg/kg/day once per day) as the first-
line treatment for neuropathic pain in children. Other drug
treatments recommended for adults may also be proposed for
this population, including topical lidocaine, in particular, as a
first-line treatment for peripheral neuropathic pain in which
the pain is localized to a particular area. In cases of insufficient
pain relief, a combination of gabapentin and amitriptyline or a
treatment switch is recommended. Psychological support and
physiotherapy to improve function and physical development
should always be proposed either on their own or as add-on
treatments. In cases of first-line treatment failure, the patient
may be referred to a pediatric chronic pain clinic. All other
drug treatments or invasive procedures should be proposed
only after interdisciplinary consultation. Further studies are
required to improve the quality of evidence for this popula-
tion, despite the difficulty of performing large-scale studies in
this context [182–184]. The possible contribution of multi-
disciplinary pain treatment programs should also be consi-
dered.
In the elderly, slow titration is particularly important for
systemic treatment [185,186]. In this population, a consensus-
based algorithm for neuropathic pain management has been
proposed, with gabapentinoids, lidocaine plasters and dulo-
xetine as first-line treatments [185]. Given the lack of specific
trials in the elderly, we propose to use this algorithm for first-
line therapy, with a switch to TCAs as the second-line
treatment, due to specific safety concerns (cardiac arrythmias
and anticholinergic effects) in this population [187].
As reported in previous meta-analyses [13,188], most
pharmacological treatments, even those proposed as first-
line treatments, are of limited efficacy, with an effect size < 0.5
[189] or a NNT > 7. There may be many reasons for this,
including drugs not necessarily been used in the right
population [4]. For this reason, an increasing number of
clinical trials in neuropathic pain are stratifying patients on
the basis of sensory phenotype or taking phenotypes into
account as secondary outcome measures for improving
treatment outcome (e.g. Demant et al., 2014, 2015; Attal
et al., 2016). In particular, lacosamide seems to be relevant for
use in patients with Nav1.7 mutation-related small-fiber
neuropathy, based on the findings of a single study [38], and
oxcarbazepine has been reported to be effective in patients
with an ‘‘irritable nociceptor’’ sensory phenotype [37]. We
strongly encourage similar studies in the future, with the aim
of targeting specific drug therapies on the basis of phenotypes
and underlying mechanisms.
Unlike previous evidence-based systematic reviews, this
review analyzed all potential drug treatments for neuropathic
pain, including those used as single administrations, such as
IV ketamine or lidocaine. These drugs are widely used at pain
centers in France, for refractory chronic neuropathic pain, in
 revue neurologique 176 (2020) 325–352
the absence of alternatives, despite considerable heteroge-
neity in terms of dose and administration route for ketamine
(‘‘OKAPI’’, Pickering, NCT03319238). The evidence for keta-
mine was considered inconclusive due to the very small
number of studies (only one) meeting our criteria, which
included, in particular, pain assessment at three weeks.
However, this does not rule out its potential benefit at earlier
time points, for up to two weeks after infusion, as reported in
previous studies (e.g. Amr, 2010). Moreover, ketamine may
also be beneficial for major depression and suicidal ideation,
which may be associated with severe pain [190]. We found no
evidence for the efficacy of single injections of IV lidocaine, but
two studies using repeated administrations gave positive
results, albeit with no long-lasting effects. Furthermore, as for
ketamine, positive results were often obtained at early time
points (1–2 weeks) in these studies, and in previous trials [191–
194]. Based on these findings and expert consensus, we
propose the use of IV ketamine or lidocaine to overcome acute
pain exacerbations in chronic neuropathic pain refractory to
more conventional medication. We strongly encourage fur-
ther well-designed studies, including long-term assessments,
for these drug treatments.
Our systematic review also encompassed all stimulation
techniques, some of which, such as TENS, are widely proposed
for neuropathic pain as a standalone therapy or in addition to
pharmacotherapy. Based on the GRADE system (recommen-
dation ‘‘weak for’’), we recommend TENS as a first-line
treatment for peripheral NP (only one studied yielded positive
results for central pain). The quality of evidence for non-
invasive brain neurostimulation (rTMS) was limited by the
lack of long-term sham-controlled assessments of analgesic
effects in most cases. Nonetheless, one sham-controlled study
based on a six-month protocol reported sustained efficacy for
motor cortex rTMS in a series of 20 patients with fibromyalgia
[195], and real-life data are also consistent with long-term
beneficial effects of motor cortex rTMS in various types of
neuropathic pain, for maintenance sessions [196–198]. We
therefore propose a weak recommendation for high-fre-
quency rTMS of the motor cortex in refractory neuropathic
pain.
Invasive therapies for neuropathic pain include pulsed
radiofrequency, intrathecal drugs, spinal cord stimulation and
epidural motor cortex stimulation. The efficacy of radio-
frequency has been confirmed by high-quality studies in a
selected population of patients with thoracic postherpetic
neuralgia. As such, it can be recommended as a third-line
treatment in this very specific population. Strikingly, although
the level of evidence for intrathecal therapy is moderate to
high in chronic pain in general, very few data were available
concerning the efficacy of this therapy specifically against
neuropathic pain, and the level of evidence was therefore
considered inconclusive [84].
Long-term prospective controlled studies of spinal cord
stimulation were conducted several years ago and the
procedure is generally considered safe, but the quality of
these studies remains moderate at best, because of the
impossibility of blinding, due to the paresthesia induced by
the stimulation. Indeed, the control group in the highest
quality study published to date had no intervention [134]. For
these reasons, the level of recommendation remains weak for
343
spinal cord stimulation for failed back surgery syndrome and
diabetic neuropathic pain. Although not evaluated in the
studies included in this analysis, there is also a potential
interest in the use of this technique for other painful
polyneuropathies. The development of new SCS techniques
using, for example, very high-frequency stimulation, which
can generate analgesia without paresthesia, should improve
the level of evidence through sham-controlled double-blind
studies, such as those beginning to emerge [139,199,200].
These sham-controlled studies highlight the importance of
the placebo effect associated with such procedures.
Epidural motor cortex stimulation (MCS) is another
invasive technique, for which a double-blind procedure is
feasible. Previous meta-analyses of MCS using less stringent
criteria concluded that the procedure was safe and probably
effective against neuropathic pain [15,201–203]. This syste-
matic review identified only one sham-controlled double-
blind study complying with our inclusion criteria: this study
had equivocal results (negative for the primary outcome and
positive for the secondary outcomes) [140]. Two other low-
quality double-blind studies with very small sample sizes
yielded positive results but did not satisfy our inclusion
criteria due to their short follow-up period [204] or retro-
spective design [205]. Therefore, in the absence of recent high-
quality studies, and based on the potential, limited risks
associated with this technique, the evidence for motor cortex
stimulation was rated as inconclusive in this recommenda-
tion. Furthermore, the availability of this technique is
restricted to a few trained surgical teams. However, open-
label studies have suggested that the outcome of the invasive
procedure might be improved by selecting candidates for
implantation according to their preoperative analgesic res-
ponse to several sessions of noninvasive high-frequency rTMS
of the motor cortex [206–209]. The use of such procedures and
the development of new designs for stimulation or electrodes
[210] are awaited, to establish the relevance of invasive motor
cortex stimulation in the routine management of neuropathic
pain.
Our recommendations also took into account psychothe-
rapies, complementary approaches, such as hypnosis or
acupuncture, and therapeutic education of the patient. These
therapies are generally included in multidisciplinary inter-
ventions, and only a very small number of the programs
widely used in clinical practice for neuropathic pain [e.g.
psychodynamic psychotherapy, hypnotherapy, eye move-
ment desensitization and reprocessing (EMDR), mindfulness]
met our inclusion criteria. Nonetheless, based on their
potential benefit in other chronic pain disorders [211–214]
and on the basis of the few available studies meeting our
requirements, we recommend CBT and mindfulness as
second-line treatments in addition to other therapies, because
of their safety, and high levels of acceptability and feasibility,
even in children or elderly patients.
5. Conclusion
The goal of these comprehensive recommendations was to
rationalize the use of all therapeutic options by general
practitioners and physicians involved in pain management in
344 revue neurologique 176 (2020) 325–352
France, and on a broader scale. The dissemination of these
guidelines will make a major contribution in this direction.
Indeed, a large study of general practitioners’ adherence to the
2010 French recommendations revealed poor recall of appro-
priate first-line drugs three years after the publication of these
guidelines [9]. We obtained similar findings for pain specialists
[7]. We hope that these recommendations will help to improve
this outcome in the next few years.
Disclosure of interest
X. Moisset has received personal fees from Teva, Novartis,
Roche, Biogen, Sanofi-Genzyme and Merck-Serono, and non-
financial support from SOS oxygene, Boehringer, Bristol Myers
Squibb, not related to the submitted work.
H. Alchaar has received honoraria from Novartis, Sanofi,
MSD, outside the submitted work in the past 5 years.
J. Avez Couturier, S. Conradi and C. Regis declare that they
have no competing interest.
D. Bouhassira has received honoraria from Grunenthal,
Novartis and Air liquide, outside the submitted work and is
participating to European projects Dolorisk and IMI PainCare.
M.H. Delmotte has received honoraria from Mylan, outside
the submitted work.
M. Lanteri-Minet received grants and honoraria for
advisory boards, speaker panels or investigation studies from
Allergan, Amgen, Astellas, ATI, BMS, Boehringer, Boston
Scientific, CoLucid, Convergence, GlaxoSmithKline, Grunen-
thal, Eli Lilly, Medtronic, Menarini, MSD, Novartis, Pfizer,
Reckitt Benckiser, Saint-Jude, Sanofi-Aventis, Teva Pharma-
ceuticals, UCB, and Zambon.
J.P. Lefaucheur has received honoraria from Novo Nordisk,
Pfizer, and Sanofi in the last 5 years, not related to the
submitted work.
G. Mick has received honoraria from Sanofi MSD, Lilly,
Pfizer, Teva, Grunenthal, Mylan, BMS UPSA outside the
submitted work in the past 5 years.
V. Piano has received honoraria from Novartis, Grünenthal,
Ethipharm, Mylan, not related to the submitted work.
G. Pickering has received honoraria from Sanofi, MSD,
Grunenthal, Mylan, Kyowa-Kirin in the last 5 years, not related
to the submitted work.
E. Piquet received honoraria from Grunenthal and Med-
tronic, not related to the submitted work.
E. Salvat has received fees from Novartis, Sanofi, Ethy-
pharm, Grunenthal, CSL Behring, MSD, Merz, Kyowa-Kirin,
Mundipharma, Mylan, Genzyme, Medtronic, Abbott and
Boston in the past 5 years, outside the submitted work.
N. Attal has received honoraria from Sanofi MSD, Sanofi-
Aventis, Sanofi Pasteur MSD, MSD vaccins, Ethypharm, Lilly
France, Grunenthal, Ipsen, Astellas, outside the submitted
work, in the past 5 years and is a member of the European
DOLORISK consortium.
Acknowledgments
We would like to thank Nathalie Pinol-Domenech and
Manuela De Carvalho for their help with the literature search.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at https://doi.org/10.1016/j.
neurol.2020.01.361.
references
[1] Doth AH, Hansson PT, Jensen MP, Taylor RS. The burden of
neuropathic pain: a systematic review and meta-analysis
of health utilities. Pain 2010;149:338–44. http://dx.doi.org/
10.1016/j.pain.2010.02.034.
[2] Attal N, Lanteri-Minet M, Laurent B, Fermanian J,
Bouhassira D. The specific disease burden of neuropathic
pain: results of a French nationwide survey. Pain
2011;152:2836–43. http://dx.doi.org/10.1016/
j.pain.2011.09.014.
[3] Langley PC, Van Litsenburg C, Cappelleri JC, Carroll D. The
burden associated with neuropathic pain in Western
Europe. J Med Econ 2013;16:85–95. http://dx.doi.org/
10.3111/13696998.2012.729548.
[4] Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson
AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis
Primer 2017;3:17002. http://dx.doi.org/10.1038/nrdp.2017.2.
[5] Dworkin RH, Malone DC, Panarites CJ, Armstrong EP,
Pham SV. Impact of postherpetic neuralgia and painful
diabetic peripheral neuropathy on health care costs. J Pain
2010;11:360–8. http://dx.doi.org/10.1016/
j.jpain.2009.08.005.
[6] Bouhassira D, Letanoux M, Hartemann A. Chronic pain
with neuropathic characteristics in diabetic patients: a
French cross-sectional study. PloS One 2013;8:e74195.
http://dx.doi.org/10.1371/journal.pone.0074195.
[7] Piano V, Lanteri-Minet M, Steegers M, Besse K, Donnet A,
Verhagen S, et al. A case vignette study to assess the
knowledge of pain physicians of neuropathic cancer pain:
room for improvement. Pain Physician 2013;16:E779–88.
[8] Torrance N, Ferguson JA, Afolabi E, Bennett MI, Serpell MG,
Dunn KM, et al. Neuropathic pain in the community: more
under-treated than refractory? Pain 2013;154:690–9. http://
dx.doi.org/10.1016/j.pain.2012.12.022.
[9] Martinez V, Attal N, Vanzo B, Vicaut E, Gautier JM,
Bouhassira D, et al. Adherence of French GPs to chronic
neuropathic pain clinical guidelines: results of a cross-
sectional, randomized, ‘‘e’’ case-vignette survey. PloS One
2014;9:e93855. http://dx.doi.org/10.1371/
journal.pone.0093855.
[10] Heutink M, Post MWM, Wollaars MM, van Asbeck FWA.
Chronic spinal cord injury pain: pharmacological and non-
pharmacological treatments and treatment effectiveness.
Disabil Rehabil 2011;33:433–40. http://dx.doi.org/10.3109/
09638288.2010.498557.
[11] Tamburin S, Lacerenza MR, Castelnuovo G, Agostini M,
Paolucci S, Bartolo M, et al. Pharmacological and non-
pharmacological strategies in the integrated treatment of
pain in neurorehabilitation. Evidence and
recommendations from the Italian Consensus Conference
on Pain in Neurorehabilitation. Eur J Phys Rehabil Med
2016;52:741–52.
[12] Martinez V, Attal N, Bouhassira D, Lantéri-Minet M. Les
douleurs neuropathiques chroniques : diagnostic,
évaluation et traitement en médecine ambulatoire.
Recommandations pour la pratique clinique de la Société
 revue neurologique 176 (2020) 325–352
française d’étude et de traitement de la douleur. Douleurs
Eval - Diagn - Trait 2010;11:3–21. http://dx.doi.org/10.1016/
j.douler.2009.12.009.
[13] Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R,
Dworkin RH, et al. Pharmacotherapy for neuropathic pain
in adults: a systematic review and meta-analysis. Lancet
Neurol 2015;14:162–73. http://dx.doi.org/10.1016/S1474-
4422(14)70251-0.
[14] Dworkin RH, O’Connor AB, Kent J, Mackey SC, Raja SN,
Stacey BR, et al. Interventional management of neuropathic
pain: NeuPSIG recommendations. Pain 2013;154:2249–61.
http://dx.doi.org/10.1016/j.pain.2013.06.004.
[15] Cruccu G, Garcia-Larrea L, Hansson P, Keindl M,
Lefaucheur J-P, Paulus W, et al. EAN guidelines on central
neurostimulation therapy in chronic pain conditions. Eur J
Neurol 2016;23:1489–99. http://dx.doi.org/10.1111/
ene.13103.
[16] Affsaps. Prise en charge médicamenteuse de la douleur
aiguë et chronique chez l’enfant; 2009.
[17] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y,
Alonso-Coello P, et al. GRADE: an emerging consensus on
rating quality of evidence and strength of
recommendations. BMJ 2008;336:924–6. http://dx.doi.org/
10.1136/bmj.39489.470347.AD.
[18] Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz
R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of
evidence. J Clin Epidemiol 2011;64:401–6. http://dx.doi.org/
10.1016/j.jclinepi.2010.07.015.
[19] Bendtsen L, Zakrzewska JM, Abbott J, Braschinsky M, Di
Stefano G, Donnet A, et al. EAN guideline on trigeminal
neuralgia. Eur J Neurol 2019. http://dx.doi.org/10.1111/
ene.13950.
[20] Brouwers M, Kho M, Browman G. AGREE II: advancing
guideline development, reporting and evaluation in health
care. CMAJ 2010;182:E839–42.
[21] Haute Autorité de santé. Méthodes d’élaboration des
recommandations de bonne pratique; 2014 [accessed May
18, 2019]https://www.has-sante.fr/portail/jcms/c_418716/
fr/methodes-d-elaboration-des-recommandations-de-
bonne-pratique.
[22] Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group.
Preferred reporting items for systematic reviews and
meta-analyses: the PRISMA statement. BMJ
2009;339:b2535.
[23] Gilron I, Tu D, Holden RR, Jackson AC, DuMerton-Shore D.
Combination of morphine with nortriptyline for
neuropathic pain. Pain 2015;156:1440–8. http://dx.doi.org/
10.1097/j.pain.0000000000000149.
[24] Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS,
Sindrup SH. Imipramine and pregabalin combination for
painful polyneuropathy: a randomized controlled trial.
Pain 2015;156:958–66. http://dx.doi.org/10.1097/
j.pain.0000000000000143.
[25] Vollmer TL, Robinson MJ, Risser RC, Malcolm SK. A
randomized, double-blind, placebo-controlled trial of
duloxetine for the treatment of pain in patients with
multiple sclerosis. Pain Pract 2014;14:732–44. http://
dx.doi.org/10.1111/papr.12127.
[26] Gao Y, Guo X, Han P, Li Q, Yang G, Qu S, et al. Treatment of
patients with diabetic peripheral neuropathic pain in
China: a double-blind randomised trial of duloxetine vs.
placebo. Int J Clin Pract 2015;69:957–66. http://dx.doi.org/
10.1111/ijcp.12641.
[27] Schukro RP, Oehmke MJ, Geroldinger A, Heinze G, Kress H-
G, Pramhas S. Efficacy of duloxetine in chronic low back
pain with a neuropathic component: a randomized,
double-blind, placebo-controlled crossover trial.
Anesthesiology 2016;124:150–8. http://dx.doi.org/10.1097/
ALN.0000000000000902.
345
[28] Enomoto H, Yasuda H, Nishiyori A, Fujikoshi S, Furukawa
M, Ishida M, et al. Duloxetine in patients with diabetic
peripheral neuropathic pain in Japan: a randomized,
double-blind, noninferiority comparative study with
pregabalin. J Pain Res 2018;11:1857–68. http://dx.doi.org/
10.2147/JPR.S170646.
[29] Harden RN, Freeman R, Rainka M, Zhang L, Bell C, Berges
A, et al. A phase 2a, randomized, crossover trial of
gabapentin enacarbil for the treatment of postherpetic
neuralgia in gabapentin inadequate responders. Pain Med
Malden Mass 2013;14:1918–32. http://dx.doi.org/10.1111/
pme.12227.
[30] Gewandter JS, Frazer ME, Cai X, Chiodo VF, Rast SA, Dugan
M, et al. Extended-release gabapentin for failed back
surgery syndrome: results from a randomized double-
blind crossover study. Pain 2019;160(5):1029–36. http://
dx.doi.org/10.1097/j.pain.0000000000001478.
[31] Mu Y, Liu X, Li Q, Chen K, Liu Y, Lv X, et al. Efficacy and
safety of pregabalin for painful diabetic peripheral
neuropathy in a population of Chinese patients: a
randomized placebo-controlled trial. J Diabetes
2018;10:256–65. http://dx.doi.org/10.1111/1753-0407.12585.
[32] Markman J, Resnick M, Greenberg S, Katz N, Yang R,
Scavone J, et al. Efficacy of pregabalin in post-traumatic
peripheral neuropathic pain: a randomized, double-blind,
placebo-controlled phase 3 trial. J Neurol 2018;265:2815–
24. http://dx.doi.org/10.1007/s00415-018-9063-9.
[33] Raskin P, Huffman C, Toth C, Asmus MJ, Messig M,
Sanchez RJ, et al. Pregabalin in patients with inadequately
treated painful diabetic peripheral neuropathy: a
randomized withdrawal trial. Clin J Pain 2014;30:379–90.
http://dx.doi.org/10.1097/AJP.0b013e31829ea1a1.
[34] Huffman C, Stacey BR, Tuchman M, Burbridge C, Li C,
Parsons B, et al. Efficacy and safety of pregabalin in the
treatment of patients with painful diabetic peripheral
neuropathy and pain on walking. Clin J Pain 2015;31:946–
58. http://dx.doi.org/10.1097/AJP.0000000000000198.
[35] Raskin P, Huffman C, Yurkewicz L, Pauer L, Scavone JM,
Yang R, et al. Pregabalin in patients with painful diabetic
peripheral neuropathy using an NSAID for other pain
conditions: a double-blind crossover study. Clin J Pain
2016;32:203–10. http://dx.doi.org/10.1097/
AJP.0000000000000254.
[36] Robertson K, Marshman LAG, Plummer D, Downs E. Effect
of gabapentin vs pregabalin on pain intensity in adults
with chronic sciatica: a randomized clinical trial. JAMA
Neurol 2019;76:28–34. http://dx.doi.org/10.1001/
jamaneurol.2018.3077.
[37] Demant DT, Lund K, Vollert J, Maier C, Segerdahl M,
Finnerup NB, et al. The effect of oxcarbazepine in
peripheral neuropathic pain depends on pain phenotype:
a randomised, double-blind, placebo-controlled
phenotype-stratified study. Pain 2014;155:2263–73. http://
dx.doi.org/10.1016/j.pain.2014.08.014.
[38] de Greef BTA, Hoeijmakers JGJ, Geerts M, Oakes M, Church
TJE, Waxman SG, et al. Lacosamide in patients with Nav1.7
mutations-related small fibre neuropathy: a randomized
controlled trial. Brain J Neurol 2019;142:263–75. http://
dx.doi.org/10.1093/brain/awy329.
[39] Corrigan R, Derry S, Wiffen PJ, Moore RA. Clonazepam for
neuropathic pain and fibromyalgia in adults. Cochrane
Database Syst Rev 2012;CD009486. http://dx.doi.org/
10.1002/14651858.CD009486.pub2.
[40] Swerdlow M, Cundill JG. Anticonvulsant drugs used in the
treatment of lancinating pain. A comparison. Anaesthesia
1981;36:1129–32. http://dx.doi.org/10.1111/j.1365-
2044.1981.tb08701.x.
[41] Simpson RW, Wlodarczyk JH. Transdermal buprenorphine
relieves neuropathic pain: a randomized, double-blind,
346 revue neurologique 176 (2020) 325–352
parallel-group, placebo-controlled trial in diabetic
peripheral neuropathic pain. Diabetes Care 2016;39:1493–
500. http://dx.doi.org/10.2337/dc16-0123.
[42] Arai T, Kashimoto Y, Ukyo Y, Tominaga Y, Imanaka K.
Two placebo-controlled, randomized withdrawal studies
to evaluate the fentanyl 1 day patch in opioid-naı̈ve
patients with chronic pain. Curr Med Res Opin
2015;31:2207–18. http://dx.doi.org/10.1185/
03007995.2015.1092127.
[43] Christoph A, Eerdekens M-H, Kok M, Volkers G,
Freynhagen R. Cebranopadol, a novel first-in-class
analgesic drug candidate: first experience in patients with
chronic low back pain in a randomized clinical trial. Pain
2017;158:1813–24. http://dx.doi.org/10.1097/
j.pain.0000000000000986.
[44] Vinik AI, Shapiro DY, Rauschkolb C, Lange B, Karcher K,
Pennett D, et al. A randomized withdrawal, placebo-
controlled study evaluating the efficacy and tolerability of
tapentadol extended release in patients with chronic
painful diabetic peripheral neuropathy. Diabetes Care
2014;37:2302–9. http://dx.doi.org/10.2337/dc13-2291.
[45] Baron R, Martin-Mola E, Müller M, Dubois C, Falke D,
Steigerwald I. Effectiveness and safety of tapentadol
prolonged release (PR) versus a combination of tapentadol
PR and pregabalin for the management of severe, chronic
low back pain with a neuropathic component: a
randomized, double-blind, phase 3b study. Pain Pract
2015;15:455–70. http://dx.doi.org/10.1111/papr.12200.
[46] Demant DT, Lund K, Finnerup NB, Vollert J, Maier C,
Segerdahl MS, et al. Pain relief with lidocaine 5% patch in
localized peripheral neuropathic pain in relation to pain
phenotype: a randomised, double-blind, and placebo-
controlled, phenotype panel study. Pain 2015;156:2234–44.
http://dx.doi.org/10.1097/j.pain.0000000000000266.
[47] Palladini M, Boesl I, Koenig S, Buchheister B, Attal N.
Lidocaine-medicated plaster, an additional potential
treatment option for localized postsurgical neuropathic
pain: efficacy and safety results of a randomized, placebo-
controlled trial. Curr Med Res Opin 2019;35:757–66. http://
dx.doi.org/10.1080/03007995.2019.1565709.
[48] Pickering G, Voute M, Macian N, Ganry H, Pereira B.
Effectiveness and safety of 5% lidocaine-medicated plaster
on localized neuropathic pain after knee surgery: a
randomized, double-blind controlled trial. Pain
2019;160:1186–95. http://dx.doi.org/10.1097/
j.pain.0000000000001502.
[49] Kiani J, Ahmad Nasrollahi S, Esna-Ashari F, Fallah P, Sajedi
F. Amitriptyline 2% cream vs. capsaicin 0.75% cream in the
treatment of painful diabetic neuropathy (double-blind,
randomized clinical trial of efficacy and safety). Iran J
Pharm Res IJPR 2015;14:1263–8.
[50] Kiani J, Sajedi F, Nasrollahi SA, Esna-Ashari F. A
randomized clinical trial of efficacy and safety of the
topical clonidine and capsaicin in the treatment of painful
diabetic neuropathy. J Res Med Sci 2015;20:359–63.
[51] Moon J-Y, Lee P-B, Kim Y-C, Lee S-C, Nahm FS, Choi E.
Efficacy and safety of 0.625% and 1.25% capsaicin patch in
peripheral neuropathic pain: multicenter, randomized,
and semi-double-blind controlled study. Pain Physician
2017;20:27–35.
[52] Simpson DM, Robinson-Papp J, Van J, Stoker M, Jacobs H,
Snijder RJ, et al. Capsaicin 8% patch in painful diabetic
peripheral neuropathy: a randomized, double-blind,
placebo-controlled study. J Pain 2017;18:42–53. http://
dx.doi.org/10.1016/j.jpain.2016.09.008.
[53] Taheri A, Farbood A, Heshmat R, Samadi A, Khashayar P,
Qorbani M, et al. The effect of transdermal nitroglycerin
on pain control in diabetic patients with peripheral
neuropathy. J Diabetes Metab Disord 2015;14:86. http://
dx.doi.org/10.1186/s40200-015-0217-3.
[54] Heydari M, Homayouni K, Hashempur MH, Shams M.
Topical Citrullus colocynthis (bitter apple) extract oil in
painful diabetic neuropathy: a double-blind randomized
placebo-controlled clinical trial. J Diabetes 2016;8:246–52.
http://dx.doi.org/10.1111/1753-0407.12287.
[55] Petramfar P, Moein M, Samani SM, Tabatabaei SH,
Zarshenas MM. Trachyspermum ammi 10% topical cream
versus placebo on neuropathic pain, a randomized,
double-blind, placebo-controlled trial. Neurol Sci
2016;37:1449–55. http://dx.doi.org/10.1007/s10072-016-
2600-3.
[56] Viswanathan V, Rajsekar S, Selvaraj B, Kumpatla S. Effect
of a polyherbal formulation cream on diabetic
neuropathic pain among patients with type 2 diabetes – A
pilot study. Indian J Med Res 2016;144:215–9. http://
dx.doi.org/10.4103/0971-5916.195033.
[57] Lynch ME, Clark AJ, Sawynok J, Sullivan MJL. Topical 2%
amitriptyline and 1% ketamine in neuropathic pain
syndromes: a randomized, double-blind, placebo-
controlled trial. Anesthesiology 2005;103:140–6.
[58] Ghasemi M, Ansari M, Basiri K, Shaigannejad V. The
effects of intradermal botulinum toxin type a injections on
pain symptoms of patients with diabetic neuropathy. J Res
Med Sci 2014;19:106–11.
[59] Attal N, de Andrade DC, Adam F, Ranoux D, Teixeira MJ,
Galhardoni R, et al. Safety and efficacy of repeated
injections of botulinum toxin A in peripheral neuropathic
pain (BOTNEP): a randomised, double-blind, placebo-
controlled trial. Lancet Neurol 2016;15:555–65. http://
dx.doi.org/10.1016/S1474-4422(16)00017-X.
[60] Han Z-A, Song DH, Oh H-M, Chung ME. Botulinum toxin
type A for neuropathic pain in patients with spinal cord
injury. Ann Neurol 2016;79:569–78. http://dx.doi.org/
10.1002/ana.24605.
[61] Rigo FK, Trevisan G, Godoy MC, Rossato MF, Dalmolin GD,
Silva MA, et al. Management of neuropathic chronic pain
with methadone combined with ketamine: a randomized,
double-blind, active-controlled clinical trial. Pain
Physician 2017;20:207–15.
[62] Serpell M, Ratcliffe S, Hovorka J, Schofield M, Taylor L,
Lauder H, et al. A double-blind, randomized, placebo-
controlled, parallel group study of THC/CBD spray in
peripheral neuropathic pain treatment. Eur J Pain
2014;18:999–1012. http://dx.doi.org/10.1002/j.1532-
2149.2013.00445.x.
[63] Schimrigk S, Marziniak M, Neubauer C, Kugler EM, Werner
G, Abramov-Sommariva D. Dronabinol is a safe long-term
treatment option for neuropathic pain patients. Eur
Neurol 2017;78:320–9. http://dx.doi.org/10.1159/000481089.
[64] Vinik A, Rosenstock J, Sharma U, Feins K, Hsu C, Merante
D, et al. Efficacy and safety of mirogabalin (DS-5565) for
the treatment of diabetic peripheral neuropathic pain: a
randomized, double-blind, placebo- and active
comparator-controlled, adaptive proof-of-concept phase 2
study. Diabetes Care 2014;37:3253–61. http://dx.doi.org/
10.2337/dc14-1044.
[65] Wang H, Romano G, Frustaci ME, Bohidar N, Ma H, Sanga
P, et al. Fulranumab for treatment of diabetic peripheral
neuropathic pain: a randomized controlled trial.
Neurology 2014;83:628–37. http://dx.doi.org/10.1212/
WNL.0000000000000686.
[66] Wang H, Romano G, Fedgchin M, Russell L, Sanga P, Kelly
KM, et al. Fulranumab in patients with pain associated
with postherpetic neuralgia and postraumatic
neuropathy: efficacy, safety, and tolerability results from a
randomized, double-blind, placebo-controlled, phase-2
 revue neurologique 176 (2020) 325–352
study. Clin J Pain 2017;33:99–108. http://dx.doi.org/10.1097/
AJP.0000000000000388.
[67] Price N, Namdari R, Neville J, Proctor KJW, Kaber S, Vest J,
et al. Safety and efficacy of a topical sodium channel
inhibitor (TV-45070) in patients with postherpetic
neuralgia (PHN): a randomized, controlled, proof-of-
concept, crossover study, with a subgroup analysis of the
Nav1.7 R1150W genotype. Clin J Pain 2017;33:310–8. http://
dx.doi.org/10.1097/AJP.0000000000000408.
[68] McDonnell A, Collins S, Ali Z, Iavarone L, Surujbally R,
Kirby S, et al. Efficacy of the Nav1.7 blocker PF-05089771 in
a randomised, placebo-controlled, double-blind clinical
study in subjects with painful diabetic peripheral
neuropathy. Pain 2018;159:1465–76. http://dx.doi.org/
10.1097/j.pain.0000000000001227.
[69] Joo YC, Ko ES, Cho JG, Ok YM, Jung GY, Kim KH.
Intravenous nefopam reduces postherpetic neuralgia
during the titration of oral medications. Korean J Pain
2014;27:54–62. http://dx.doi.org/10.3344/
kjp.2014.27.1.54.
[70] Wiffen PJ, Knaggs R, Derry S, Cole P, Phillips T, Moore RA.
Paracetamol (acetaminophen) with or without codeine or
dihydrocodeine for neuropathic pain in adults. Cochrane
Database Syst Rev 2016;12:CD012227. http://dx.doi.org/
10.1002/14651858.CD012227.pub2.
[71] Moore RA, Chi C-C, Wiffen PJ, Derry S, Rice ASC. Oral
nonsteroidal anti-inflammatory drugs for neuropathic
pain. Cochrane Database Syst Rev 2015;CD010902. http://
dx.doi.org/10.1002/14651858.CD010902.pub2.
[72] Fallon MT, Wilcock A, Kelly CA, Paul J, Lewsley L-A, Norrie
J, et al. Oral ketamine vs placebo in patients with cancer-
related neuropathic pain: a randomized clinical trial.
JAMA Oncol 2018;4:870–2. http://dx.doi.org/10.1001/
jamaoncol.2018.0131.
[73] Viola V, Newnham HH, Simpson RW. Treatment of
intractable painful diabetic neuropathy with intravenous
lignocaine. J Diabetes Complications 2006;20:34–9. http://
dx.doi.org/10.1016/j.jdiacomp.2005.05.007.
[74] Kim Y-C, Castañeda AM, Lee C-S, Jin H-S, Park KS, Moon
JY. Efficacy and safety of lidocaine infusion treatment for
neuropathic pain: a randomized, double-blind, and
placebo-controlled study. Reg Anesth Pain Med
2018;43:415–24. http://dx.doi.org/10.1097/
AAP.0000000000000741.
[75] Moulin DE, Morley-Forster PK, Pirani Z, Rohfritsch C, Stitt
L. Intravenous lidocaine in the management of chronic
peripheral neuropathic pain: a randomized controlled
trial. Can J Anaesth J Can Anesth 2019. http://dx.doi.org/
10.1007/s12630-019-01395-8.
[76] Amr YM. Multi-day low dose ketamine infusion as
adjuvant to oral gabapentin in spinal cord injury related
chronic pain: a prospective, randomized, double-blind
trial. Pain Physician 2010;13:245–9.
[77] Buesing S, Costa M, Schilling JM, Moeller-Bertram T.
Vitamin B12 as a treatment for pain. Pain Physician
2019;22:E45–52.
[78] Eker HE, Cok OY, Aribogan A, Arslan G. Management of
neuropathic pain with methylprednisolone at the site of
nerve injury. Pain Med Malden Mass 2012;13:443–51.
http://dx.doi.org/10.1111/j.1526-4637.2011.01323.x.
[79] Labat JJ, Riant T, Lassaux A, Rioult B, Rabischong B,
Khalfallah M, et al. Adding corticosteroids to the pudendal
nerve block for pudendal neuralgia: a randomised, double-
blind, controlled trial. BJOG Int J Obstet Gynaecol
2017;124:251–60. http://dx.doi.org/10.1111/1471-
0528.14222.
[80] Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka
M, Yodono M, et al. Intrathecal methylprednisolone for
intractable postherpetic neuralgia. N Engl J Med
347
2000;343:1514–9. http://dx.doi.org/10.1056/
NEJM200011233432102.
[81] Rijsdijk M, van Wijck AJM, Meulenhoff PCW, Kavelaars A,
van der Tweel I, Kalkman CJ. No beneficial effect of
intrathecal methylprednisolone acetate in postherpetic
neuralgia patients. Eur J Pain Lond Engl 2013;17:714–23.
http://dx.doi.org/10.1002/j.1532-2149.2012.00233.x.
[82] Rijsdijk M, Svensson CI, Wijck AJvan, Kalkman CJ, Yaksh
TL. Analgesic properties of intrathecal glucocorticoids in
three well established preclinical pain models. Scand J
Pain 2016;10:90–102. http://dx.doi.org/10.1016/
j.sjpain.2015.10.006.
[83] Dureja GP, Usmani H, Khan M, Tahseen M, Jamal A.
Efficacy of intrathecal midazolam with or without
epidural methylprednisolone for management of post-
herpetic neuralgia involving lumbosacral dermatomes.
Pain Physician 2010;13:213–21.
[84] Deer TR, Pope JE, Hayek SM, Bux A, Buchser E, Eldabe S,
et al. The Polyanalgesic Consensus Conference (PACC):
recommendations on intrathecal drug infusion systems
best practices and guidelines. Neuromodulation J Int
Neuromodulation Soc 2017;20:96–132. http://dx.doi.org/
10.1111/ner.12538.
[85] Deer TR, Pope JE, Hanes MC, McDowell GC. Intrathecal
therapy for chronic pain: a review of morphine and
ziconotide as first-line options. Pain Med Malden Mass
2019;20:784–98. http://dx.doi.org/10.1093/pm/pny132.
[86] Rutgers M, van Romunde L, Osman P. A small randomized
comparative trial of acupuncture versus transcutaneous
electrical neurostimulation in postherpetic neuralgia. Pain
Clin 1988;2:87–9.
[87] Kumar D, Marshall HJ. Diabetic peripheral neuropathy:
amelioration of pain with transcutaneous
electrostimulation. Diabetes Care 1997;20:1702–5.
[88] Ghoname EA, White PF, Ahmed HE, Hamza MA, Craig WF,
Noe CE. Percutaneous electrical nerve stimulation: an
alternative to TENS in the management of sciatica. Pain
1999;83:193–9.
[89] Barbarisi M, Pace MC, Passavanti MB, Maisto M,
Mazzariello L, Pota V, et al. Pregabalin and transcutaneous
electrical nerve stimulation for postherpetic neuralgia
treatment. Clin J Pain 2010;26:567–72. http://dx.doi.org/
10.1097/AJP.0b013e3181dda1ac.
[90] Gossrau G, Wähner M, Kuschke M, Konrad B, Reichmann
H, Wiedemann B, et al. Microcurrent transcutaneous
electric nerve stimulation in painful diabetic neuropathy:
a randomized placebo-controlled study. Pain Med Malden
Mass 2011;12:953–60. http://dx.doi.org/10.1111/j.1526-
4637.2011.01140.x.
[91] Buchmuller A, Navez M, Milletre-Bernardin M, Pouplin S,
Presles E, Lantéri-Minet M, et al. Value of TENS for relief of
chronic low back pain with or without radicular pain. Eur J
Pain Lond Engl 2012;16:656–65. http://dx.doi.org/10.1002/
j.1532-2149.2011.00061.x.
[92] Koca I, Boyaci A, Tutoglu A, Ucar M, Kocaturk O.
Assessment of the effectiveness of interferential current
therapy and TENS in the management of carpal tunnel
syndrome: a randomized controlled study. Rheumatol Int
2014;34:1639–45. http://dx.doi.org/10.1007/s00296-014-
3005-3.
[93] Bi X, Lv H, Chen B-L, Li X, Wang X-Q. Effects of
transcutaneous electrical nerve stimulation on pain in
patients with spinal cord injury: a randomized controlled
trial. J Phys Ther Sci 2015;27:23–5. http://dx.doi.org/
10.1589/jpts.27.23.
[94] Naderi Nabi B, Sedighinejad A, Haghighi M, Biazar G,
Hashemi M, Haddadi S, et al. Comparison of
transcutaneous electrical nerve stimulation and pulsed
radiofrequency sympathectomy for treating painful
348 revue neurologique 176 (2020) 325–352
diabetic neuropathy. Anesthesiol Pain Med 2015;5:e29280.
http://dx.doi.org/10.5812/aapm.29280.
[95] Xu G, Xú G, Feng Y, Tang WZ, Lv ZW. Transcutaneous
electrical nerve stimulation in combination with
cobalamin injection for postherpetic neuralgia: a single-
center randomized controlled trial. Am J Phys Med Rehabil
2014;93:287–98. http://dx.doi.org/10.1097/
PHM.0000000000000002.
[96] Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ,
Hayat G, et al. Static magnetic field therapy for
symptomatic diabetic neuropathy: a randomized, double-
blind, placebo-controlled trial. Arch Phys Med Rehabil
2003;84:736–46.
[97] Wróbel MP, Szymborska-Kajanek A, Wystrychowski G,
Biniszkiewicz T, Sieroń-Stołtny K, Sieroń A, et al. Impact of
low frequency pulsed magnetic fields on pain intensity,
quality of life and sleep disturbances in patients with
painful diabetic polyneuropathy. Diabetes Metab
2008;34:349–54. http://dx.doi.org/10.1016/
j.diabet.2008.02.003.
[98] Weintraub MI, Herrmann DN, Smith AG, Backonja MM,
Cole SP. Pulsed electromagnetic fields to reduce diabetic
neuropathic pain and stimulate neuronal repair: a
randomized controlled trial. Arch Phys Med Rehabil
2009;90:1102–9. http://dx.doi.org/10.1016/
j.apmr.2009.01.019.
[99] Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni
MC, et al. Effectiveness of frequency-modulated
electromagnetic neural stimulation in the treatment of
painful diabetic neuropathy. Diabetologia 2005;48:817–23.
http://dx.doi.org/10.1007/s00125-005-1734-2.
[100] Bosi E, Bax G, Scionti L, Spallone V, Tesfaye S, Valensi P,
et al. Frequency-modulated electromagnetic neural
stimulation (FREMS) as a treatment for symptomatic
diabetic neuropathy: results from a double-blind,
randomised, multicentre, long-term, placebo-controlled
clinical trial. Diabetologia 2013;56:467–75. http://
dx.doi.org/10.1007/s00125-012-2795-7.
[101] Kang BS, Shin HI, Bang MS. Effect of repetitive transcranial
magnetic stimulation over the hand motor cortical area
on central pain after spinal cord injury. Arch Phys Med
Rehabil 2009;90:1766–71. http://dx.doi.org/10.1016/
j.apmr.2009.04.008.
[102] Ahmed MA, Mohamed SA, Sayed D. Long-term antalgic
effects of repetitive transcranial magnetic stimulation of
motor cortex and serum beta-endorphin in patients with
phantom pain. Neurol Res 2011;33:953–8. http://dx.doi.org/
10.1179/1743132811Y.0000000045.
[103] Hosomi K, Shimokawa T, Ikoma K, Nakamura Y,
Sugiyama K, Ugawa Y, et al. Daily repetitive transcranial
magnetic stimulation of primary motor cortex for
neuropathic pain: a randomized, multicenter, double-
blind, crossover, sham-controlled trial. Pain
2013;154:1065–72. http://dx.doi.org/10.1016/
j.pain.2013.03.016.
[104] Khedr EM, Kotb HI, Mostafa MG, Mohamad MF, Amr
SA, Ahmed MA, et al. Repetitive transcranial magnetic
stimulation in neuropathic pain secondary to
malignancy: a randomized clinical trial. Eur J Pain
Lond Engl 2015;19:519–27. http://dx.doi.org/10.1002/
ejp.576.
[105] Ma S-M, Ni J-X, Li X-Y, Yang L-Q, Guo Y-N, Tang Y-Z. High-
frequency repetitive transcranial magnetic stimulation
reduces pain in postherpetic neuralgia. Pain Med Malden
Mass 2015;16:2162–70. http://dx.doi.org/10.1111/
pme.12832.
[106] Malavera A, Silva FA, Fregni F, Carrillo S, Garcia RG.
Repetitive transcranial magnetic stimulation for phantom
limb pain in land mine victims: a double-blinded,
randomized, sham-controlled trial. J Pain 2016;17:911–8.
http://dx.doi.org/10.1016/j.jpain.2016.05.003.
[107] Pei Q, Wu B, Tang Y, Yang X, Song L, Wang N, et al.
Repetitive transcranial magnetic stimulation at different
frequencies for postherpetic neuralgia: a double-blind,
sham-controlled, randomized trial. Pain Physician
2019;22:E303–13.
[108] Onesti E, Gabriele M, Cambieri C, Ceccanti M, Raccah R, Di
Stefano G, et al. H-coil repetitive transcranial magnetic
stimulation for pain relief in patients with diabetic
neuropathy. Eur J Pain Lond Engl 2013;17:1347–56. http://
dx.doi.org/10.1002/j.1532-2149.2013.00320.x.
[109] de Oliveira RAA, de Andrade DC, Mendonça M, Barros R,
Luvisoto T, Myczkowski ML, et al. Repetitive transcranial
magnetic stimulation of the left premotor/dorsolateral
prefrontal cortex does not have analgesic effect on central
poststroke pain. J Pain 2014;15:1271–81. http://dx.doi.org/
10.1016/j.jpain.2014.09.009.
[110] Galhardoni R, Aparecida da Silva V, Garcı́a-Larrea L, Dale
C, Baptista AF, Barbosa LM, et al. Insular and anterior
cingulate cortex deep stimulation for central neuropathic
pain: disassembling the percept of pain. Neurology
2019;92:e2165–7. http://dx.doi.org/10.1212/
WNL.0000000000007396.
[111] Mori F, Codecà C, Kusayanagi H, Monteleone F, Buttari F,
Fiore S, et al. Effects of anodal transcranial direct current
stimulation on chronic neuropathic pain in patients with
multiple sclerosis. J Pain 2010;11:436–42. http://dx.doi.org/
10.1016/j.jpain.2009.08.011.
[112] Wrigley PJ, Gustin SM, McIndoe LN, Chakiath RJ,
Henderson LA, Siddall PJ. Longstanding neuropathic pain
after spinal cord injury is refractory to transcranial direct
current stimulation: a randomized controlled trial. Pain
2013;154:2178–84. http://dx.doi.org/10.1016/
j.pain.2013.06.045.
[113] Lewis GN, Rice DA, Kluger M, McNair PJ. Transcranial
direct current stimulation for upper limb neuropathic
pain: a double-blind randomized controlled trial. Eur J
Pain Lond Engl 2018;22:1312–20. http://dx.doi.org/10.1002/
ejp.1220.
[114] Berra E, Bergamaschi R, De Icco R, Dagna C, Perrotta A,
Rovaris M, et al. The effects of transcutaneous spinal
direct current stimulation on neuropathic pain in multiple
sclerosis: clinical and neurophysiological assessment.
Front Hum Neurosci 2019;13:31. http://dx.doi.org/10.3389/
fnhum.2019.00031.
[115] Tan G, Rintala DH, Thornby JI, Yang J, Wade W, Vasilev C.
Using cranial electrotherapy stimulation to treat pain
associated with spinal cord injury. J Rehabil Res Dev
2006;43:461–74.
[116] Tan G, Rintala DH, Jensen MP, Richards JS, Holmes SA,
Parachuri R, et al. Efficacy of cranial electrotherapy
stimulation for neuropathic pain following spinal cord
injury: a multi-site randomized controlled trial with a
secondary 6-month open-label phase. J Spinal Cord Med
2011;34:285–96. http://dx.doi.org/10.1179/
2045772311Y.0000000008.
[117] Chang MC. Efficacy of pulsed radiofrequency stimulation
in patients with peripheral neuropathic pain: a narrative
review. Pain Physician 2018;21:E225–34.
[118] Geurts JWM, van Wijk RMAW, Wynne HJ, Hammink E,
Buskens E, Lousberg R, et al. Radiofrequency lesioning of
dorsal root ganglia for chronic lumbosacral radicular pain:
a randomised, double-blind, controlled trial. Lancet Lond
Engl 2003;361:21–6.
[119] Van Zundert J, Patijn J, Kessels A, Lamé I, van Suijlekom H,
van Kleef M. Pulsed radiofrequency adjacent to the
cervical dorsal root ganglion in chronic cervical radicular
pain: a double-blind sham-controlled randomized clinical
 revue neurologique 176 (2020) 325–352
trial. Pain 2007;127:173–82. http://dx.doi.org/10.1016/
j.pain.2006.09.002.
[120] Simopoulos TT, Kraemer J, Nagda JV, Aner M, Bajwa ZH.
Response to pulsed and continuous radiofrequency
lesioning of the dorsal root ganglion and segmental nerves
in patients with chronic lumbar radicular pain. Pain
Physician 2008;11:137–44.
[121] Ke M, Yinghui F, Yi J, Xeuhua H, Xiaoming L, Zhijun C,
et al. Efficacy of pulsed radiofrequency in the treatment of
thoracic postherpetic neuralgia from the angulus costae: a
randomized, double-blinded, controlled trial. Pain
Physician 2013;16:15–25.
[122] Shanthanna H, Chan P, McChesney J, Thabane L, Paul J.
Pulsed radiofrequency treatment of the lumbar dorsal root
ganglion in patients with chronic lumbar radicular pain: a
randomized, placebo-controlled pilot study. J Pain Res
2014;7:47–55. http://dx.doi.org/10.2147/JPR.S55749.
[123] Koh W, Choi S-S, Karm MH, Suh JH, Leem JG, Lee JD, et al.
Treatment of chronic lumbosacral radicular pain using
adjuvant pulsed radiofrequency: a randomized controlled
study. Pain Med Malden Mass 2015;16:432–41. http://
dx.doi.org/10.1111/pme.12624.
[124] Makharita MY, Amr YM. Pulsed radiofrequency for
chronic inguinal neuralgia. Pain Physician 2015;18:E147–
55.
[125] Chang MC, Cho YW, Ahn SH. Comparison between bipolar
pulsed radiofrequency and monopolar pulsed
radiofrequency in chronic lumbosacral radicular pain: a
randomized controlled trial. Medicine (Baltimore)
2017;96:e6236. http://dx.doi.org/10.1097/
MD.0000000000006236.
[126] Halim W, van der Weegen W, Lim T, Wullems JA, Vissers
KC. Percutaneous cervical nucleoplasty vs. pulsed radio
frequency of the dorsal root ganglion in patients with
contained cervical disk herniation; a prospective,
randomized controlled trial. Pain Pract 2017;17:729–37.
http://dx.doi.org/10.1111/papr.12517.
[127] Luo F, Wang T, Shen Y, Meng L, Lu J, Ji N. High voltage
pulsed radiofrequency for the treatment of refractory
neuralgia of the infraorbital nerve: a prospective double-
blinded randomized controlled study. Pain Physician
2017;20:271–9.
[128] Wang F, Zhou Q, Xiao L, Yang J, Xong D, Li D, et al. A
randomized comparative study of pulsed radiofrequency
treatment with or without selective nerve root block for
chronic cervical radicular pain. Pain Pract 2017;17:589–95.
http://dx.doi.org/10.1111/papr.12493.
[129] Makharita MY, El Bendary HM, Sonbul ZM, Ahmed SES,
Latif MA. Ultrasound-guided pulsed radiofrequency in the
management of thoracic postherpetic neuralgia: a
randomized, double-blinded, controlled trial. Clin J Pain
2018;34:1017–24. http://dx.doi.org/10.1097/
AJP.0000000000000629.
[130] Hamza MA, White PF, Craig WF, Ghoname ES, Ahmed HE,
Proctor TJ, et al. Percutaneous electrical nerve stimulation:
a novel analgesic therapy for diabetic neuropathic pain.
Diabetes Care 2000;23:365–70.
[131] Deer T, Pope J, Benyamin R, Vallejo R, Friedman A,
Caraway D, et al. Prospective, multicenter, randomized,
double-blinded, partial crossover study to assess the
safety and efficacy of the novel neuromodulation system
in the treatment of patients with chronic pain of
peripheral nerve origin. Neuromodulation J Int
Neuromodulation Soc 2016;19:91–100. http://dx.doi.org/
10.1111/ner.12381.
[132] Deer TR, Levy RM, Kramer J, Poree L, Amirdelfan K, Grigsby
E, et al. Dorsal root ganglion stimulation yielded higher
treatment success rate for complex regional pain
syndrome and causalgia at 3 and 12 months: a
349
randomized comparative trial. Pain 2017;158:669–81.
http://dx.doi.org/10.1097/j.pain.0000000000000814.
[133] North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord
stimulation versus repeated lumbosacral spine surgery for
chronic pain: a randomized, controlled trial. Neurosurgery
2005;56:98–106. http://dx.doi.org/10.1227/
01.neu.0000144839.65524.e0 [discussion 106–107].
[134] Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J,
et al. Spinal cord stimulation versus conventional medical
management for neuropathic pain: a multicentre
randomised controlled trial in patients with failed back
surgery syndrome. Pain 2007;132:179–88. http://dx.doi.org/
10.1016/j.pain.2007.07.028.
[135] de Vos CC, Meier K, Zaalberg PB, Nijhuis HJA, Duyvendak
W, Vesper J, et al. Spinal cord stimulation in patients with
painful diabetic neuropathy: a multicentre randomized
clinical trial. Pain 2014;155:2426–31. http://dx.doi.org/
10.1016/j.pain.2014.08.031.
[136] Slangen R, Schaper NC, Faber CG, Joosten EA, Dirksen CD,
van Dongen RT, et al. Spinal cord stimulation and pain
relief in painful diabetic peripheral neuropathy: a
prospective two-center randomized controlled trial.
Diabetes Care 2014;37:3016–24. http://dx.doi.org/10.2337/
dc14-0684.
[137] Kapural L, Yu C, Doust MW, Gliner BE, Vallejo R, Sitzman
BT, et al. Novel 10-kHz high-frequency therapy (HF10
Therapy) is superior to traditional low-frequency spinal
cord stimulation for the treatment of chronic back and leg
pain: the SENZA-RCT randomized controlled trial.
Anesthesiology 2015;123:851–60. http://dx.doi.org/10.1097/
ALN.0000000000000774.
[138] Bolash R, Creamer M, Rauck R, Vahedifar P, Calodney A,
Fox I, et al. Wireless high-frequency spinal cord
stimulation (10 kHz) compared with multiwaveform low-
frequency spinal cord stimulation in the management of
chronic pain in failed back surgery syndrome subjects:
preliminary results of a multicenter, prospective
randomized controlled study. Pain Med 2019;20(10):1971–
9. http://dx.doi.org/10.1093/pm/pnz019.
[139] Al-Kaisy A, Palmisani S, Pang D, Sanderson K, Wesley S,
Tan Y, et al. Prospective, randomized, sham-control,
double-blind, crossover trial of subthreshold spinal cord
stimulation at various kilohertz frequencies in subjects
suffering from failed back surgery syndrome (SCS
Frequency Study). Neuromodulation J Int
Neuromodulation Soc 2018;21:457–65. http://dx.doi.org/
10.1111/ner.12771.
[140] Lefaucheur J-P, Drouot X, Cunin P, Bruckert R, Lepetit H,
Créange A, et al. Motor cortex stimulation for the
treatment of refractory peripheral neuropathic pain. Brain
J Neurol 2009;132:1463–71. http://dx.doi.org/10.1093/brain/
awp035.
[141] Robert R, Labat J-J, Bensignor M, Glemain P, Deschamps C,
Raoul S, et al. Decompression and transposition of the
pudendal nerve in pudendal neuralgia: a randomized
controlled trial and long-term evaluation. Eur Urol
2005;47:403–8. http://dx.doi.org/10.1016/
j.eururo.2004.09.003.
[142] Gerdesmeyer L, Wagenpfeil S, Birkenmaier C, Veihelmann
A, Hauschild M, Wagner K, et al. Percutaneous epidural
lysis of adhesions in chronic lumbar radicular pain: a
randomized, double-blind, placebo-controlled trial. Pain
Physician 2013;16:185–96.
[143] Macaré van Maurik JFM, van Hal M, van Eijk RPA, Kon M,
Peters EJG. Value of surgical decompression of
compressed nerves in the lower extremity in patients with
painful diabetic neuropathy: a randomized controlled
trial. Plast Reconstr Surg 2014;134:325–32. http://
dx.doi.org/10.1097/PRS.0000000000000369.
350 revue neurologique 176 (2020) 325–352
[144] Lindblad K, Bergkvist L, Johansson A-C. Evaluation of the
treatment of chronic chemotherapy-induced peripheral
neuropathy using long-wave diathermy and interferential
currents: a randomized controlled trial. Support Care
Cancer 2016;24:2523–31. http://dx.doi.org/10.1007/s00520-
015-3060-7.
[145] Sindou M, Mertens P, Wael M. Microsurgical DREZotomy
for pain due to spinal cord and/or cauda equina injuries:
long-term results in a series of 44 patients. Pain
2001;92:159–71. http://dx.doi.org/10.1016/s0304-
3959(00)00487-5.
[146] Aichaoui F, Mertens P, Sindou M. Dorsal root entry zone
lesioning for pain after brachial plexus avulsion: results
with special emphasis on differential effects on the
paroxysmal versus the continuous components. A
prospective study in a 29-patient consecutive series. Pain
2011;152:1923–30. http://dx.doi.org/10.1016/
j.pain.2011.03.037.
[147] Evans S, Fishman B, Spielman L, Haley A. Randomized
trial of cognitive behavior therapy versus supportive
psychotherapy for HIV-related peripheral neuropathic
pain. Psychosomatics 2003;44:44–50. http://dx.doi.org/
10.1176/appi.psy.44.1.44.
[148] Heutink M, Post MWM, Bongers-Janssen HMH, Dijkstra
CA, Snoek GJ, Spijkerman DCM, et al. The CONECSI trial:
results of a randomized controlled trial of a
multidisciplinary cognitive behavioral program for coping
with chronic neuropathic pain after spinal cord injury.
Pain 2012;153:120–8. http://dx.doi.org/10.1016/
j.pain.2011.09.029.
[149] Knoerl R, Smith EML, Barton DL, Williams DA, Holden JE,
Krauss JC, et al. Self-guided online cognitive behavioral
strategies for chemotherapy-induced peripheral
neuropathy: a multicenter, pilot, randomized, wait-list
controlled trial. J Pain 2018;19:382–94. http://dx.doi.org/
10.1016/j.jpain.2017.11.009.
[150] Meize-Grochowski R, Shuster G, Boursaw B, DuVal M,
Murray-Krezan C, Schrader R, et al. Mindfulness
meditation in older adults with postherpetic neuralgia: a
randomized controlled pilot study. Geriatr Nurs N Y N
2015;36:154–60. http://dx.doi.org/10.1016/
j.gerinurse.2015.02.012.
[151] Nathan HJ, Poulin P, Wozny D, Taljaard M, Smyth C, Gilron
I, et al. Randomized trial of the effect of mindfulness-
based stress reduction on pain-related disability, pain
intensity, health-related quality of life, and A1C in
patients with painful diabetic peripheral neuropathy. Clin
Diabetes Publ Am Diabetes Assoc 2017;35:294–304. http://
dx.doi.org/10.2337/cd17-0077.
[152] Gok Metin Z, Arikan Donmez A, Izgu N, Ozdemir L, Arslan
IE. Aromatherapy massage for neuropathic pain and
quality of life in diabetic patients. J Nurs Scholarsh
2017;49:379–88. http://dx.doi.org/10.1111/jnu.12300.
[153] Estores I, Chen K, Jackson B, Lao L, Gorman PH. Auricular
acupuncture for spinal cord injury related neuropathic
pain: a pilot controlled clinical trial. J Spinal Cord Med
2017;40:432–8. http://dx.doi.org/10.1080/
10790268.2016.1141489.
[154] Anwar S, Mowafy Z, Ali Z, Hamed H. Visual Analogue and
Neuropathic Pain Scales response to low level laser in
cases of postherpetic neuralgia of the sciatic nerve. Int J
PharmTech Res 2016;9:30–6.
[155] Rajanandh MG, Kosey S, Prathiksha G. Assessment of
antioxidant supplementation on the neuropathic pain
score and quality of life in diabetic neuropathy patients – a
randomized controlled study. Pharmacol Rep 2014;66:44–
8. http://dx.doi.org/10.1016/j.pharep.2013.08.003.
[156] Vitamin E in Neuroprotection Study (VENUS)
Investigators, Hor CP, Fung WY, Ang HA, Lim SC, Kam LY,
et al. Efficacy of oral mixed tocotrienols in diabetic
peripheral neuropathy: a randomized clinical trial. JAMA
Neurol 2018;75:444–52. http://dx.doi.org/10.1001/
jamaneurol.2017.4609.
[157] Toth C, Brady S, Gagnon F, Wigglesworth K. A
randomized, single-blind, controlled, parallel assignment
study of exercise versus education as adjuvant in the
treatment of peripheral neuropathic pain. Clin J Pain
2014;30:111–8. http://dx.doi.org/10.1097/
AJP.0b013e31828ccd0f.
[158] Barbin J, Seetha V, Casillas JM, Paysant J, Pérennou D. The
effects of mirror therapy on pain and motor control of
phantom limb in amputees: a systematic review. Ann
Phys Rehabil Med 2016;59:270–5. http://dx.doi.org/10.1016/
j.rehab.2016.04.001.
[159] Thompson T, Terhune DB, Oram C, Sharangparni J, Rouf R,
Solmi M, et al. The effectiveness of hypnosis for pain
relief: a systematic review and meta-analysis of 85
controlled experimental trials. Neurosci Biobehav Rev
2019;99:298–310. http://dx.doi.org/10.1016/
j.neubiorev.2019.02.013.
[160] Vickers AJ, Vertosick EA, Lewith G, MacPherson H, Foster
NE, Sherman KJ, et al. Acupuncture for chronic pain:
update of an individual patient data meta-analysis. J Pain
2018;19:455–74. http://dx.doi.org/10.1016/
j.jpain.2017.11.005.
[161] Brown S, Johnston B, Amaria K, Watkins J, Campbell F,
Pehora C, et al. A randomized controlled trial of
amitriptyline versus gabapentin for complex regional pain
syndrome type I and neuropathic pain in children. Scand J
Pain 2016;13:156–63. http://dx.doi.org/10.1016/
j.sjpain.2016.05.039.
[162] Lebrun C, Vukusic S, French Group for Recommendations
in Multiple Sclerosis (France4MS), the Société
francophone de la sclérose en plaques (SFSEP).
Immunization and multiple sclerosis: recommendations
from the French Multiple Sclerosis Society. Rev Neurol
(Paris) 2019;175:341–57. http://dx.doi.org/10.1016/
j.neurol.2019.04.001.
[163] Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al.
GRADE guidelines: 1. Introduction-GRADE evidence
profiles and summary of findings tables. J Clin Epidemiol
2011;64:383–94. http://dx.doi.org/10.1016/
j.jclinepi.2010.04.026.
[164] Attal N, Fermanian C, Fermanian J, Lanteri-Minet M,
Alchaar H, Bouhassira D. Neuropathic pain: are there
distinct subtypes depending on the aetiology or
anatomical lesion? Pain 2008;138:343–53. http://dx.doi.org/
10.1016/j.pain.2008.01.006.
[165] Baron R, Maier C, Attal N, Binder A, Bouhassira D, Cruccu
G, et al. Peripheral neuropathic pain: a mechanism-related
organizing principle based on sensory profiles. Pain
2017;158:261–72. http://dx.doi.org/10.1097/
j.pain.0000000000000753.
[166] Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I,
Serpell M. 5% lidocaine-medicated plaster versus
pregabalin in post-herpetic neuralgia and diabetic
polyneuropathy: an open-label, non-inferiority two-stage
RCT study. Curr Med Res Opin 2009;25:1663–76. http://
dx.doi.org/10.1185/03007990903047880.
[167] Haanpää M, Cruccu G, Nurmikko TJ, McBride WT, Docu
Axelarad A, Bosilkov A, et al. Capsaicin 8% patch versus
oral pregabalin in patients with peripheral neuropathic
pain. Eur J Pain Lond Engl 2016;20:316–28. http://
dx.doi.org/10.1002/ejp.731.
[168] Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T,
Bouhassira D, et al. Duloxetine and pregabalin: high-dose
monotherapy or their combination? The ‘‘COMBO-DN
study’’ – a multinational, randomized, double-blind,
 revue neurologique 176 (2020) 325–352
parallel-group study in patients with diabetic peripheral
neuropathic pain. Pain 2013;154:2616–25. http://
dx.doi.org/10.1016/j.pain.2013.05.043.
[169] Gomes T, Juurlink DN, Antoniou T, Mamdani MM,
Paterson JM, van den Brink W. Gabapentin, opioids, and
the risk of opioid-related death: a population-based
nested case-control study. PLoS Med 2017;14:e1002396.
http://dx.doi.org/10.1371/journal.pmed.1002396.
[170] Mathieson S, Maher CG, McLachlan AJ, Latimer J, Koes BW,
Hancock MJ, et al. Trial of pregabalin for acute and chronic
sciatica. N Engl J Med 2017;376:1111–20. http://dx.doi.org/
10.1056/NEJMoa1614292.
[171] Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of
pregabalin and gabapentin. Drugs 2017;77:403–26. http://
dx.doi.org/10.1007/s40265-017-0700-x.
[172] Mick G, Gillet D, Heritier C, Garcia-Porra C, Bochet E.
[Prescription and uses of pregabalin: analysis of a cohort
of 419 patients at a pain study and treatment centre, and
literature review]. Douleur Analg 2019;32:87–94.
[173] Molero Y, Larsson H, D’Onofrio BM, Sharp DJ, Fazel S.
Associations between gabapentinoids and suicidal
behaviour, unintentional overdoses, injuries, road traffic
incidents, and violent crime: population-based cohort
study in Sweden. BMJ 2019;365:l2147. http://dx.doi.org/
10.1136/bmj.l2147.
[174] Crossin R, Scott D, Arunogiri S, Smith K, Dietze PM,
Lubman DI. Pregabalin misuse-related ambulance
attendances in Victoria, 2012–2017: characteristics of
patients and attendances. Med J Aust 2019;210:75–9.
http://dx.doi.org/10.5694/mja2.12036.
[175] Driot D, Jouanjus E, Oustric S, Dupouy J, Lapeyre-Mestre M.
Patterns of gabapentin and pregabalin use and misuse:
results of a population-based cohort study in France. Br J
Clin Pharmacol 2019;85:1260–9. http://dx.doi.org/10.1111/
bcp.13892.
[176] Nahar LK, Murphy KG, Paterson S. Misuse and mortality
related to gabapentin and pregabalin are being under-
estimated: a two-year post-mortem population study. J
Anal Toxicol 2019;43(7):564–70. http://dx.doi.org/10.1093/
jat/bkz036.
[177] Moisset X, Trouvin A-P, Tran V-T, Authier N, Vergne-Salle
P, Piano V, et al. [Use of strong opioids in chronic non-
cancer pain in adults. Evidence-based recommendations
from the French Society for the Study and Treatment of
Pain]. Presse Med 2016;45:447–62. http://dx.doi.org/
10.1016/j.lpm.2016.02.014.
[178] ANSM. État des lieux de la consommation des antalgiques
opioı̈des et leurs usages problématiques; 2019 [accessed
July 19, 2019]https://ansm.sante.fr/S-informer/Points-d-
information-Points-d-information/Antalgiques-opioides-
l-ANSM-publie-un-etat-des-lieux-de-la-consommation-
en-France-Point-d-Information.
[179] Stoicea N, Costa A, Periel L, Uribe A, Weaver T, Bergese SD.
Current perspectives on the opioid crisis in the US
healthcare system: a comprehensive literature review.
Medicine (Baltimore) 2019;98:e15425. http://dx.doi.org/
10.1097/MD.0000000000015425.
[180] Chenaf C, Kaboré J-L, Delorme J, Pereira B, Mulliez A,
Zenut M, et al. Prescription opioid analgesic use in France:
trends and impact on morbidity-mortality. Eur J Pain Lond
Engl 2019;23:124–34. http://dx.doi.org/10.1002/ejp.1291.
[181] ANSM. Cannabis à visée thérapeutique en France; 2019.
[182] Boulkedid R, Abdou AY, Desselas E, Monégat M, de Leeuw
TG, Avez-Couturier J, et al. The research gap in chronic
paediatric pain: a systematic review of randomised
controlled trials. Eur J Pain Lond Engl 2018;22:261–71.
http://dx.doi.org/10.1002/ejp.1137.
[183] de Leeuw TG, Mangiarini L, Lundin R, Kaguelidou F, van
der Zanden T, Pasqua OD, et al. Gabapentin as add-on to
351
morphine for severe neuropathic or mixed pain in
children from age 3 months to 18 years – evaluation of the
safety, pharmacokinetics, and efficacy of a new
gabapentin liquid formulation: study protocol for a
randomized controlled trial. Trials 2019;20:49. http://
dx.doi.org/10.1186/s13063-018-3169-3.
[184] Kaguelidou F, Le Roux E, Mangiarini L, Lundin R, de
Leeuw TG, Della Pasqua O, et al. Non-inferiority double-
blind randomised controlled trial comparing gabapentin
versus tramadol for the treatment of chronic
neuropathic or mixed pain in children and adolescents:
the GABA-1 trial – a study protocol. BMJ Open
2019;9:e023296. http://dx.doi.org/10.1136/bmjopen-
2018-023296.
[185] Pickering G, Marcoux M, Chapiro S, David L, Rat P, Michel
M, et al. An algorithm for neuropathic pain management
in older people. Drugs Aging 2016;33:575–83. http://
dx.doi.org/10.1007/s40266-016-0389-7.
[186] Capriz F, Chapiro S, David L, Floccia M, Guillaumé C, Moel
V, et al. Consensus multidisciplinaire d’experts en douleur
et gériatrie : utilisation des antalgiques dans la prise en
charge de la douleur de la personne âgée (hors
anesthésie). Douleurs Eval - Diagn - Trait 2017;18:234–47.
[187] Sultana J, Spina E, Trifirò G. Antidepressant use in the
elderly: the role of pharmacodynamics and
pharmacokinetics in drug safety. Expert Opin Drug Metab
Toxicol 2015;11:883–92. http://dx.doi.org/10.1517/
17425255.2015.1021684.
[188] Finnerup NB, Haroutounian S, Baron R, Dworkin RH,
Gilron I, Haanpaa M, et al. Neuropathic pain clinical trials:
factors associated with decreases in estimated drug
efficacy. Pain 2018;159:2339–46. http://dx.doi.org/10.1097/
j.pain.0000000000001340.
[189] Cohen J. Statistical power analysis for the behavioral
sciences. 2nd ed. L. Erlbaum Associates, New-Jersey, USA;
1988.
[190] Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough
JW, Feder A, et al. The effect of a single dose of
intravenous ketamine on suicidal ideation: a systematic
review and individual participant data meta-analysis. Am
J Psychiatry 2018;175:150–8. http://dx.doi.org/10.1176/
appi.ajp.2017.17040472.
[191] Kastrup J, Petersen P, Dejgård A, Angelo HR, Hilsted J.
Intravenous lidocaine infusion – a new treatment of
chronic painful diabetic neuropathy? Pain 1987;28:69–75.
[192] Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D.
Systemic lidocaine in pain due to peripheral nerve injury
and predictors of response. Neurology 2004;62:218–25.
http://dx.doi.org/10.1212/01.wnl.0000103237.62009.77.
[193] Tremont-Lukats IW, Hutson PR, Backonja M-M. A
randomized, double-masked, placebo-controlled pilot trial
of extended IV lidocaine infusion for relief of ongoing
neuropathic pain. Clin J Pain 2006;22:266–71. http://
dx.doi.org/10.1097/01.ajp.0000169673.57062.40.
[194] Liu H, Lu F, Zhou D, Yin Y, Li J, Yang B, et al. The analgesic
and emotional response to intravenous lidocaine infusion
in the treatment of postherpetic neuralgia: a randomized,
double-blinded, placebo-controlled study. Clin J Pain
2018;34:1025–31. http://dx.doi.org/10.1097/
AJP.0000000000000623.
[195] Mhalla A, Baudic S, Ciampi de Andrade D, Gautron M,
Perrot S, Teixeira MJ, et al. Long-term maintenance of the
analgesic effects of transcranial magnetic stimulation in
fibromyalgia. Pain 2011;152:1478–85. http://dx.doi.org/
10.1016/j.pain.2011.01.034.
[196] Hodaj H, Alibeu J-P, Payen J-F, Lefaucheur J-P. Treatment
of chronic facial pain including cluster headache by
repetitive transcranial magnetic stimulation of the motor
cortex with maintenance sessions: a naturalistic study.
352 revue neurologique 176 (2020) 325–352
Brain Stimulat 2015;8:801–7. http://dx.doi.org/10.1016/
j.brs.2015.01.416.
[197] Kobayashi M, Fujimaki T, Mihara B, Ohira T. Repetitive
transcranial magnetic stimulation once a week induces
sustainable long-term relief of central poststroke pain.
Neuromodulation J Int Neuromodulation Soc 2015;18:249–
54. http://dx.doi.org/10.1111/ner.12301.
[198] Quesada C, Pommier B, Fauchon C, Bradley C, Créac’h C,
Vassal F, et al. Robot-guided neuronavigated repetitive
transcranial magnetic stimulation (rTMS) in central
neuropathic pain. Arch Phys Med Rehabil 2018. http://
dx.doi.org/10.1016/j.apmr.2018.04.013.
[199] Perruchoud C, Eldabe S, Batterham AM, Madzinga G,
Brookes M, Durrer A, et al. Analgesic efficacy of high-
frequency spinal cord stimulation: a randomized double-
blind placebo-controlled study. Neuromodulation Technol
Neural Interface 2013;16:363–9. http://dx.doi.org/10.1111/
ner.12027.
[200] Duarte RV, Nevitt S, McNicol E, Taylor RS, Buchser E, North
RB, et al. Systematic review and meta-analysis of placebo/
sham-controlled randomised trials of spinal cord
stimulation for neuropathic pain. Pain 2019;160(1):24–35.
http://dx.doi.org/10.1097/j.pain.0000000000001689.
[201] Lima MC, Fregni F. Motor cortex stimulation for chronic
pain: systematic review and meta-analysis of the
literature. Neurology 2008;70:2329–37. http://dx.doi.org/
10.1212/01.wnl.0000314649.38527.93.
[202] Fontaine D, Hamani C, Lozano A. Efficacy and safety of
motor cortex stimulation for chronic neuropathic pain:
critical review of the literature. J Neurosurg 2009;110:251–
6. http://dx.doi.org/10.3171/2008.6.17602.
[203] Nguyen JP, Lefaucheur JP, Raoul S, Roualdes V, Péréon Y,
Keravel Y. Chapter 40 – Motor cortex stimulation for the
treatment of neuropathic pain. In: Krames ES, Hunter
Peckham P, Rezai AR, editors. Neuromodulation. San
Diego: Academic Press; 2009. p. 515–26.
[204] Nguyen J-P, Velasco F, Brugières P, Velasco M, Keravel Y,
Boleaga B, et al. Treatment of chronic neuropathic pain by
motor cortex stimulation: results of a bicentric controlled
crossover trial. Brain Stimulat 2008;1:89–96. http://
dx.doi.org/10.1016/j.brs.2008.03.007.
[205] Rasche D, Ruppolt M, Stippich C, Unterberg A, Tronnier
VM. Motor cortex stimulation for long-term relief of
chronic neuropathic pain: a 10-year experience. Pain
2006;121:43–52. http://dx.doi.org/10.1016/
j.pain.2005.12.006.
[206] Hosomi K, Saitoh Y, Kishima H, Oshino S, Hirata M, Tani
N, et al. Electrical stimulation of primary motor cortex
within the central sulcus for intractable neuropathic pain.
Clin Neurophysiol 2008;119:993–1001. http://dx.doi.org/
10.1016/j.clinph.2007.12.022.
[207] Lefaucheur J-P, Ménard-Lefaucheur I, Goujon C, Keravel Y,
Nguyen J-P. Predictive value of rTMS in the identification
of responders to epidural motor cortex stimulation
therapy for pain. J Pain 2011;12:1102–11. http://dx.doi.org/
10.1016/j.jpain.2011.05.004.
[208] André-Obadia N, Mertens P, Lelekov-Boissard T, Afif A,
Magnin M, Garcia-Larrea L. Is life better after motor cortex
stimulation for pain control? Results at long-term and
their prediction by preoperative rTMS. Pain Physician
2014;17:53–62.
[209] Pommier B, Quesada C, Fauchon C, Nuti C, Vassal F,
Peyron R. Added value of multiple versus single sessions
of repetitive transcranial magnetic stimulation in
predicting motor cortex stimulation efficacy for refractory
neuropathic pain. J Neurosurg 2019;130:1750–61. http://
dx.doi.org/10.3171/2017.12.JNS171333.
[210] Khatoun A, Asamoah B, Mc Laughlin M. Investigating the
feasibility of epicranial cortical stimulation using
concentric-ring electrodes: a novel minimally invasive
neuromodulation method. Front Neurosci 2019;13:773.
http://dx.doi.org/10.3389/fnins.2019.00773.
[211] Hilton L, Hempel S, Ewing BA, Apaydin E, Xenakis L,
Newberry S, et al. Mindfulness meditation for chronic
pain: systematic review and meta-analysis. Ann Behav
Med Publ Soc Behav Med 2017;51:199–213. http://
dx.doi.org/10.1007/s12160-016-9844-2.
[212] Hughes LS, Clark J, Colclough JA, Dale E, McMillan D.
Acceptance and commitment therapy (ACT) for chronic
pain: a systematic review and meta-analyses. Clin J Pain
2017;33:552–68. http://dx.doi.org/10.1097/
AJP.0000000000000425.
[213] de Vries F, Bruin M, Lobatto DJ, Dekkers OM, Schoones JW,
van Furth WR, et al. Opioids and their endocrine effects: a
systematic review and meta-analysis. J Clin Endocrinol
Metab 2019;105(3). http://dx.doi.org/10.1210/jcemdgz022.
[214] Farrar JT, Young JP, LaMoreaux L, Werth JL, Poole RM.
Clinical importance of changes in chronic pain intensity
measured on an 11-point numerical pain rating scale. Pain
2001;94:149–58. http://dx.doi.org/10.1016/s0304-
3959(01)00349-9.