Pain Ther (2021) 10:315–332

https://doi.org/10.1007/s40122-021-00252-1

REVIEW

Analgesic Effect of Noninvasive Brain Stimulation

for Neuropathic Pain Patients: A Systematic Review
Kun-Long Zhang . Hua Yuan . Fei-Fei Wu . Xue-Yin Pu .
Bo-Zhi Liu . Ze Li . Kai-Feng Li . Hui Liu . Yi Yang . Ya-Yun Wang

Received: December 24, 2020 / Accepted: February 26, 2021 / Published online: March 22, 2021
Ó The Author(s) 2021

ABSTRACT reviews were excluded first, and those related to

animal studies or involving healthy volunteers
Introduction: The objective of this review is to were also excluded. Finally, 29 studies covering
systematically summarize the consensus on best 826 NP patients were reviewed.
practices for different NP conditions of the two Results: The results from the 24 enrolled stud-
most commonly utilized noninvasive brain ies and 736 NP patients indicate that rTMS
stimulation (NIBS) technologies, repetitive successfully relieved the pain symptoms of 715
transcranial magnetic stimulation (rTMS), and (97.1%) NP patients. Also, five studies involving
transcranial direct current stimulation (tDCS). 95 NP patients (81.4%) also showed that tDCS
Methods: PubMed was searched according to successfully relieved NP. In the included stud-
the predetermined keywords and criteria. Only ied, the M1 region plays a key role in the anal-
English language studies and studies published gesic treatment of NIBS. The motor evoked
up to January 31, 2020 were taken into consid- potentials (MEPs), the 10–20 electroen-
eration. Meta-analyses, reviews, and systematic cephalography system (EEG 10/20 system), and
neuro-navigation methods are used in clinical
practice to locate therapeutic targets. Based on
K.-L. Zhang
F.-F. Wu
X.-Y. Pu
B.-Z. Liu
Z. Li
the results of the review, the stimulation
K.-F. Li
H. Liu
Y. Yang
Y.-Y. Wang (&)
Specific Lab for Mitochondrial Plasticity Underlying parameters of rTMS that best induce an anal-
Nervous System Diseases, National Demonstration gesic effect are a stimulation frequency of
Center for Experimental Preclinical Medicine 10–20 Hz, a stimulation intensity of 80–120% of
Education, Air Force Medical University, Xi’an RMT, 1000–2000 pulses, and 5–10 sessions, and
710032, China
e-mail: wangyy@fmmu.edu.cn the most effective parameters of tDCS are a
current intensity of 2 mA, a session duration of
K.-L. Zhang
H. Yuan 20–30 min, and 5–10 sessions.
Department of Rehabilitation Medicine, Xi-Jing
Conclusions: Our systematically reviewed the
Hospital, Air Force Medical University, Xi’an
710032, China evidence for positive and negative responses to
rTMS and tDCS for NP patient care and under-
H. Liu
Y. Yang scores the analgesic efficacy of NIBS in patients
Department of Human Anatomy, Yan-An
University, Yan’an 716000, China with NP. The treatment of NP should allow the
design of optimal treatments for individual
Y.-Y. Wang patients.
State Key Laboratory of Military Stomatology,
School of Stomatology, The Fourth Military Medical
University, Xi’an, China
316 Pain Ther (2021) 10:315–332

Keywords: Neuropathic pain; Noninvasive commonly utilized technologies, repetitive

brain stimulation; Repetitive transcranial transcranial magnetic stimulation (rTMS) and
magnetic stimulation; Review; Transcranial transcranial direct current stimulation (tDCS)
direct current stimulation [9]. NIBS guidelines for the clinic are key for
making patient care decisions in rehabilitation
procedures, but no consensus of best practices
Key Summary Points
for different NP conditions currently exists
[10–16]. Therefore, we systematically reviewed
Neuropathic pain (NP) in this review is
the evidence for positive and negative responses
categorized as typical NP (TNP) resulting
to rTMS and tDCS for NP patient care.
from diabetes, stroke, spinal cord injury
(SCI) and nerve lesions, and special NP
(SNP), including facial NP (FaNP), cancer METHODS
NP (CaNP), phantom limb NP (PhanNP),
and other malformations. Literature Search Strategy
Commonly used parameters of rTMS were
a stimulation frequency of 10–20 Hz, a Studies published up to January 31, 2020 were
stimulation intensity of 80–120% of the taken into consideration for obtaining relevant
resting motor threshold, 1000–2000 literature findings. A PubMed search for articles
pulses, and 5–10 sessions. published in and after 2010 with keywords
‘‘rTMS/tDCS AND neuropathic pain’’ identified
The most common parameters of tDCS 237 studies from different countries. The refer-
were a current intensity of 2 mA, a session ence lists of articles that met the eligibility cri-
duration of 20–30 min, and 5–10 sessions. teria were further screened to identify
additional studies that may fall within the scope
of this review.

Inclusion and Exclusion Criteria

DIGITAL FEATURES and Screening Process

This article is published with digital features, Based on the abstracts of the studies, we first
including a summary slide, to facilitate under- made an initial judgement on the 237 studies
standing of the article. To view digital features that might be of value, including only English
for this article go to https://doi.org/10.6084/ language studies and excluding meta-analyses,
m9.figshare.14105999. reviews, and systematic reviews. For the
remaining 162 studies, after reviewing the full
text and excluding animal studies and studies of
INTRODUCTION healthy volunteers, we made a final decision on
which studies should be included in the review.
Neuropathic pain (NP) has been defined by the
In other words, studies eligible to be included in
International Association for the Study of Pain
this review had to meet the following inclusion
as pain caused by a lesion or disease of the
criteria: (1) only English language studies were
somatosensory system [1–3]. A treatment that
included; (2) meta-analyses, reviews, and sys-
addresses the dynamic neural system changes in
tematic reviews were excluded; (3) animal
NP is needed. Noninvasive brain stimulation
studies were excluded; (4) studies involving
(NIBS) is one such promising therapeutic tech-
healthy volunteers were excluded.
nique [4].
Finally, 29 studies covering 826 NP patients
NIBS is based on the interaction of electricity
were reviewed here. The summary on search
or magnetism with the body [5–8] (Fig. 1). Pre-
strategy can be seen in Fig. 2. Through reading
sent NIBS techniques include the two most
Pain Ther (2021) 10:315–332 317

Fig. 1 Origin and development of NIBS. NIBS is based on the interaction of electricity or magnetism with the body. The
historically important events related to brain electric or magnetic stimulation were indicated

the full text, we grasped the situation of NP limb pain, cancerous pain, malformation, and
patients in the 29 studies. In addition to bladder pain syndrome. It should be noticed,
counting the number of patients, we also made however, that the most common cases of NP are
a statistical summary according to the treat- the following four types including (1) stroke, (2)
ment situation of NIBS, the targeted sites, and spinal cord injury, (3) nerve injury, and (4)
the different treatment parameters. This article diabetic neuropathy, which have been named
is based on previously conducted studies and as typical NP (TNP) in the manuscript. While
does not contain any new studies with human the remaining types of NP have been named as
participants or animals performed by any of the special NP (SNP), including (1) facial pain, (2)
authors. Written informed consent was phantom limb pain, (3) cancerous pain, and (4)
obtained for the use of the two patients’ pho- others (malformation and bladder pain syn-
tographs in this publication. drome), because of the low incidences of such
NP. The present classification could help the
Data Synthesis clinician deeply understand the analgesic effect
of noninvasive brain stimulation for both typi-
This study used aggregate data where possible, cal and special NP.
in accordance with the Preferred Reporting In addition, according to the positive or
Items for Systematic Reviews and Meta-Analysis negative effect of NIBS on NP in all reports, all
(PRISMA) guidelines [17]. NP patients can be divided into four categories:
(1) rTMS-P, all NP patients with a positive
analgesic effect from rTMS treatment; (2) rTMS-
Categories of NP in the Present Review
N, all NP patients with a negative analgesic
effect from rTMS treatment; (3) tDCS-P, all NP
NP is classified as central or peripheral based on patients with a positive analgesic effect from
the anatomical location of the injury or disease tDCS treatment; (4) tDCS-N, all NP patients
[18]. Central NP is due to a lesion or disease of with a negative analgesic effect from tDCS
the spinal cord and/or brain, the most common treatment.
causes of which include stroke and spinal cord The patients with NP have different symp-
injury. In the present review, nine types of NP toms such as paroxysmal pain, hyperalgesia,
have been studied. Among them, two types of and allodynia. An increased sensation of pain in
NP belong to the central NP, including stroke response to a normally painful stimulus is ter-
and spinal cord injury, while seven types of NP med hyperalgesia, which can be assessed using
belong to the peripheral NP, including diabetic painful thermal (cold or heat) or punctate (e.g.,
neuropathy, nerve injury, facial pain, phantom pinprick) stimuli whether patients have
318 Pain Ther (2021) 10:315–332

Fig. 2 PRISMA (Preferred Reporting Items for Systematic studies covering 826 NP patients were reviewed here.
Reviews and Meta-Analysis) flow diagram. A PubMed Instead of using the classic central and peripheral classi-
search for articles published in and after 2010 with fications, we classified the most common (large number of
keywords ‘ rTMS/tDCS AND neuropathic pain’’ identified cases) types of NP as typical NP (TNP), including diabetic
237 studies from different countries. Meta-analyses, neuropathy, stroke, spinal cord injury (SCI), and nerve
reviews, and systematic reviews were excluded. Among injury. The remaining clinically rare types are classified as
the 162 filtered studies, those related to animal studies or special NP (SNP), such as facial pain, phantom limb pain,
involving healthy volunteers were excluded. Finally, 29 cancer pain, and other types of pain

improved hyperalgesia or allodynia after NIBS RESULTS

treatment [1]. The analgesic effects of rTMS or
tDCS on NP patients are based on a total of Analgesic Effect of NIBS on TNP and SNP
eight kinds of NP screening tools including the
Visual Analog Scale (VAS) [14, 19–32], Numeric
As shown in Table 1, the results from the 24
Rating Scale (NRS) [33–41], Neuropathic Pain
enrolled studies and 736 NP patients indicate
Questionnaire (NPQ) [30], Visual Numerical
that rTMS successfully relieved the pain symp-
Scale (VNS) [42], Quantitative Sensory Testing
toms of 715 (97.1%) NP patients. Only 21 NP
(QST) [31], Verbal Descriptor Scale (VDS) [32]
patients (2.9%) did not experience pain relief, as
and McGill Pain Questionnaire/Short-Form
reported by De Oliveira RA et al. [30]. Among
McGill Pain Questionnaire (MPQ/SF-MPQ)
715 NP patients who experienced a significant
[23, 30]. Pain relief is generally defined as an
analgesic effect of rTMS, 68.8% (n = 492) had
improvement of more than 20% in the pain
TNP, while 31.2% (n = 223) had SNP.
score [1].
As also outlined in Table 1, a total of six
articles and 125 NP patients were involved in
tDCS treatment. Among them, five studies
Pain Ther (2021) 10:315–332 319

Table 1 Summary of the 29 manuscripts of analgesic effects by NIBS (both rTMS and tDCS) on NP patients
NP patients (n) TNP patients (n) SNP patients (n)
NIBS Stimulati Total NP
Ref Diabetic/Stroke/SCI FaNP/CaNP/PhanNP Analgesic Effect
Type on Target patients(n) TNP/SNP
/Nerve /others

1. Galhardonl R et al., [36] rTMS ACC / PSI 98 98 / 0 0 / 98 / 0 / 0 0/0/0/0 Pain relief by NRS

Ander-Obadia N et al.,
2. rTMS M1 32 20 / 12 0 / 12 / 5 / 3 12 / 0 / 0 / 0 Pain relief by NRS
[37]
40% Pain relief by
3. Benjamin P et al., [19] rTMS M1 12 9/3 0/7/2/0 0/0/1/2
VAS

4. Nizard J et al., [35] rTMS DLPFC 1 0/1 0/0/0/0 0/0/0/1 Pain relief by NRS

Pain relief by
5. KOHúTOVá B et al., [31] rTMS M1 19 0 / 19 0/0/0/0 19 / 0 / 0 / 0
VAS/QST

6. Shimizu T et al., [20] rTMS M1 18 18 / 0 1 / 12 / 5 / 0 0/0/0/0 Pain relief by VAS

7. Ayache SS et al., [26] rTMS M1 66 50 / 16 0 / 17 / 11 / 22 16 / 0 / 0 / 0 Pain relief by VAS

Pain relief
8. Malavera A et al., [14] rTMS M1 54 0 / 54 0/0/0/0 0 / 0 / 54 / 0
by VAS

9. Hodaj H et al., [42] rTMS M1 55 0 / 55 0/0/0/0 55 / 0 / 0 / 0 Pain relief by VNS

41% pain relief by

10. Pommier B et al., [21] rTMS M1 40 40 / 0 0 / 0 / 0 / 40 0/0/0/0
VAS
Pain relief by VDS
11. Khedr EM et al., [32] rTMS M1 24 0 / 24 0/0/0/0 0 / 24 / 0 / 0
/ VAS
S1 / M1
12. Lindholm P et al., [34] rTMS 16 0 / 16 0/0/0/0 16 / 0 / 0 / 0 Pain relief by NRS
and S2
40% Pain relief by
13. Nizrad J et al., [38] rTMS M1 2 0/2 0/0/0/0 0/2/0/0
NRS
Modest pain relief
14. Hosomi K et al., [22] rTMS M1 64 60 / 4 0 / 52 / 7 / 2 0/0/3/0
by VAS

15. Onesti E et al., [28] rTMS M1 25 25 / 0 25 / 0 / 0 / 0 0/0/0/0 Pain relief by VAS

16. JETTé F et al., [33] rTMS M1 16 16 / 0 0 / 0 / 16 / 0 0/0/0/0 Pain relief by NRS

41% pain relief by

17. Lefaucheur JP et al., [23] rTMS M1 14 11 / 3 0/8/0/3 3/0/0/0 VAS and 31% SF-
MPQ

18. Lefaucheur JP et al., [24] rTMS M1 59 44 / 15 0 / 20 / 12 / 12 15 / 0 / 0 / 0 Pain relief by VAS

50% Pain relief by

19. Sampson SM et al., [29] rTMS DLPFC 9 2/7 0/0/1/1 0/0/2/5
VAS
25% Pain relief by
20. Di Rollo A et al., [45] rTMS M1 1 0/1 0/0/0/0 0/0/1/0
VAS

21. Lefaucheur JP et al., [27] rTMS M1 32 32 / 0 0 / 10 / 6 / 16 0/0/0/0 Pain relief by VAS

50.9% Pain relief

22. Picarelli H et al., [25] rTMS M1 23 23 / 0 0 / 0 / 0 / 23 0/0/0/0
by VAS
No pain relief by
De Oliveira RA et al., PMC /
23. rTMS 21 21 / 0 0 / 21 / 0 / 0 0/0/0/0 VAS / MPQ /
[30] DLPFC
NPQ
rTMS rTMS & DCS:
24. Attal N et al., [39] M1 35 35 / 0 0 / 0 / 0 / 35 0/0/0/0
/ tDCS Pain relief by NRS

25. Houde F et al., [44] tDCS M1 1 0/1 0/0/0/0 0/0/0/1 Pain relief by VAS

26. Bolognini N et al., [16] tDCS M1 8 0/8 0/0/0/0 0/0/8/0 Pain relief by VAS

27. Soler MD et al., [40] tDCS M1 39 39 / 0 0 / 0 / 39 / 0 0/0/0/0 Pain relief by NRS

28. Antal A et al., [43] tDCS M1 12 1 / 11 0/1/0/0 5/0/1/5 Pain relief by VAS

No pain relief by
29. Jensen MP et al., [41] tDCS M1 30 30 / 0 0 / 0 / 30 / 0 0/0/0/0
NRS

Studies of rTMS treatment are labeled yellow, studies of tDCS treatment are labeled green, and studies of ineffective
treatment are labeled gray
rTMS repetitive transcranial magnetic stimulation, tDCS transcranial direct current stimulation, ACC anterior cingulate
cortex, PSI posterior superior insula, M1 primary motor cortex, DLPFC dorsolateral prefrontal cortex, PMC premotor
cortex, S1 primary somatosensory cortex, S2 secondary somatosensory cortex
320 Pain Ther (2021) 10:315–332

involving 95 NP patients (76.0%) also showed TNP induced by SCI (65.7%, n = 69), lesions of
that tDCS successfully relieved NP the nerve trunks or roots (33.3%, n = 35), and
[39, 40, 43, 44]. Thirty NP patients (24.0%) did stroke (1.0%, n = 1). There were no patients
not experience pain relief, as reported by Jensen with TNP induced by diabetic neuropathy
MP et al. [41]. Among 95 NP patients who (n = 0).
experienced a significant analgesic effect of
tDCS, 81 had TNP (85.3%) and 14 had SNP Stroke-Induced TNP
(14.7%). Stroke-induced NP occurs in 2–8% of stroke
survivors, with a prevalence of up to 18% in
TNP patients with somatosensory deficits and about
half of the lesions affect solely the spinothala-
As shown in Fig. 3, among 575 patients with mic pathway, which may severely impair their
TNP, 505 received rTMS treatment for TNP quality of life [19, 36, 46]. Among NIBS-treated
induced by stroke (50.9%, n = 257), nerve trunk patients with stroke-induced TNP (n = 258)
or root legions (30.9%, n = 156), SCI (12.9%, (Fig. 3), most were rTMS-P (91.5%, n = 236), and
n = 65), and diabetic neuropathy (5.3%, n = 27). only one patient was tDCS-P (3.9%, n = 1).
Furthermore, among the 575 patients with TNP, Unfortunately, 21 patients were rTMS-N (8.1%).
105 patients received tDCS treatment, including However, no reports described cases of tDCS-N

negative treatment results. All NP patients can be divided

Fig. 3 Effect of NIBS on different subtypes of TNP. The into four categories: (1) rTMS-P, all NP patients with a
figure shows the therapeutic effect of NIBS on four positive analgesic effect from rTMS treatment; (2) rTMS-
subtypes of typical NP (TNP) (above): (1) stroke (blue), N, all NP patients with a negative analgesic effect from
(2) spinal cord injury (SCI) (red), (3) nerve trunk or root rTMS treatment; (3) tDCS-P, all NP patients with a
lesions (green), and (4) diabetes (purple). In the same positive analgesic effect from tDCS treatment; and (4)
subtype of data (below), the dark color represents the tDCS-N, all NP patients with a negative analgesic effect
positive treatment results and the light color represents the from tDCS treatment
Pain Ther (2021) 10:315–332 321

(n = 0). This result may imply that rTMS is imply that NIBS is effective for damaged nerve-
effective in refractory and drug-resistant post- induced NP, which would be of benefit to NIBS
stroke NP, although this conclusion deserves supporters and victims of drug-resistant NP.
confirmation in larger replication studies.
SNP
SCI-Induced TNP As shown in Fig. 4, among 251 patients with
SCI-induced NP ranks among the most debili- SNP, 92.0% (n = 231) received rTMS treatment,
tating complications of traumatic SCI, affect- and only 8.0% (n = 20) received tDCS treat-
ing [ 80% of patients within 5 years after ment. Among the 231 rTMS-treated SNP
trauma and leading to NP in up to 59% of patients (Fig. 4), 58.9% (n = 136) had FaNP,
individuals [36]. Among the NIBS-treated 11.3% (n = 26) had CaNP, 26.4% (n = 61) had
patients with TNP induced by SCI (n = 134) PhanNP, and others (3.4%, n = 8). Among the
(Fig. 3), half were rTMS-P (48.5%, n = 65), and 20 tDCS-treated SNP patients, 25.0% (n = 5) had
nearly one-third were tDCS-P (29.1%, n = 39). FaNP, 45.0% (n = 9) had PhanNP, others
Unfortunately, 30 were tDCS-N (22.4%). No (30.0%, n = 6) and none (n = 0) had CaNP.
reports described cases of rTMS-N (n = 0). This
result may imply that rTMS is a reliable treat- FaNP
ment for SCI-induced NP. However, the appli- NIBS has not been frequently studied in
cation of tDCS treatment for SCI-induced TNP patients with FaNP until now. As shown in
patients may need much more careful Fig. 4, in total, among the 141 FaNP patients,
assessment. most were rTMS-P (96.5%, n = 136), and some
were tDCS-P (3.5%, n = 5). There were no cases
Diabetic Neuropathy-Induced TNP of either rTMS-N (n = 0) or tDCS-N (n = 0).
Diabetic NP is the most common peripheral Previous literature data concerning 86 patients
neuropathy globally, and its principal pathol- with FaNP [31, 37, 42] indicate that motor cor-
ogy involves distal autonomic and sensory tex rTMS provides transient and modest sub-
dysfunction, predominantly affecting the jective pain relief. Hodaj et al. [42] have
patient’s feet, estimated to affect approximately reported that that in 55 patients (cluster head-
30% of people with diabetes [47]. Among NIBS- ache, n = 19; trigeminal NP, n = 21; atypical
treated diabetic TNP patients (n = 27) (Fig. 3), facial pain, n = 15), three pain measures (in-
all of them were rTMS-P (100%). There were no tensities of permanent pain and paroxysmal
cases of rTMS-N (n = 0), tDCS-P (n = 0), or tDCS- pain and daily number of painful attacks) were
N (n = 0). This result, however, does not indi- significantly decreased. Therefore, this result
cate that rTMS is most suitable for this type of could imply that NIBS is suitable for FaNP
NP because of the limited number of clinical patients in the clinic.
trials. We can only advocate caution when we
encounter this kind of complicated pain CaNP
condition. CaNP may arise from nerve compression or
direct infiltration by a growing tumor or sec-
Nerve Lesion-Induced TNP ondarily from changes in the neuronal media
Lesions of the nerve can affect peripheral resulting from cancer and is difficult to control
nerves, plexus trunks, or spinal nerve roots, [32]. As shown in Fig. 4, among the 26 CaNP
causing paralysis, paresthesia, and pain [21, 48]. patients, all were rTMS-P (100%). There were no
Among NIBS-treated patients with TNP induced cases of rTMS-N (n = 0), tDCS-P (n = 0), or tDCS-
by lesions of the nerve trunks or roots (n = 191) N (n = 0). Therefore, the present results indicate
(Fig. 3), most of them were rTMS-P (81.7%, the potential efficacy of rTMS for CaNP patients.
n = 156), and some were tDCS-P (18.3%,
n = 35). There were no cases of either rTMS-N
(n = 0) or tDCS-N (n = 0). This result could
322 Pain Ther (2021) 10:315–332

Fig. 4 Effect of NIBS on different subtypes of SNP. The represents the negative treatment results. All NP patients
figure shows the therapeutic effect of NIBS on four can be divided into four categories: (1) rTMS-P, all NP
subtypes of special NP (SNP) (above): (1)facial NP patients with a positive analgesic effect from rTMS
(FaNP) (blue), (2) phantom limb NP (PhanNP) (red), (3) treatment; (2) rTMS-N, all NP patients with a negative
cancer NP (CaNP) (green), and (4) other conditions analgesic effect from rTMS treatment; (3) tDCS-P, all NP
(purple), such as malformation, and bladder pain syn- patients with a positive analgesic effect from tDCS
drome. In the same subtype of data (below), the dark color treatment; and (4) tDCS-N, all NP patients with a
represents the positive treatment results and the light color negative analgesic effect from tDCS treatment

PhanNP tDCS-P (42.9%, n = 6). There are no cases of

PhanNP is very common after limb amputation either rTMS-N (n = 0) or tDCS-N (n = 0). This
and difficult to treat, usually responding poorly result could reflect the fact that rTMS could not
to conventional pain treatments [45]. As shown relieve pain effectively in some clinical trials,
in Fig. 4, among the 70 PhanNP patients, most and tDCS could be attempted and potentially
were rTMS-P (87.1%, n = 61), and 12.% were effective.
tDCS-P (n = 9). There were no cases of rTMS-N
(n = 0) or tDCS-N (n = 0). Nevertheless, the Analgesic Target and Localization of rTMS
positive analgesic effects of NIBS deserve further
research in a large number of populations
As shown in Table 1 and Fig. 3, among the 484
experiencing NP in an amputated limb.
TNP patients with rTMS-P, 79.4% (n = 384) of
the rTMS treatments targeted M1, 10.1%
Other SNPs (n = 49) targeted the anterior cingulate cortex
Other conditions, such as complex regional (ACC), 10.1% (n = 49) targeted the posterior
pain syndrome (CRPS) [44], fibromyalgia, or superior insula (PSI), and 0.4% (n = 2) targeted
polyneuropathy [41], can also cause NP. Among the dorsolateral prefrontal cortex (DLPFC).
NIBS-treated patients with TNP induced by As shown in Table 1 and Fig. 4, among the
other sources (n = 14) (Fig. 4), most of them 231 SNP patients with rTMS-P, almost all
were rTMS-P (57.1%, n = 8), and some were (96.5%, n = 223) were administered rTMS that
Pain Ther (2021) 10:315–332 323

targeted M1, and only 3.5% (n = 8) received the EEG 10/20 system) to target M1 contralat-
rTMS that targeted the DLPFC. There are no eral to the painful side [16, 39–41, 52]. This
reports on SNP patients with a positive response method is simple and convenient and is also
to rTMS targeting other brain regions. This may widely used in clinical practice.
suggest that for NP patients with FaNP, CaNP,
or PhanNP, M1-targeted rTMS should be the Neuro-Navigation Method
first choice. A 1 9 1 9 1 mm3 3D T1-weighted MRI for
As mentioned above, 79.4% of effective frameless stereotaxic neuro-navigation can be
analgesia targeted M1 (Table 1), which means used to define the target of magnetic stimula-
that the M1 region plays a key role in the tion, for example, the subdivision of M1 repre-
analgesic treatment of NIBS. Therefore, it is senting the hand [53, 54] (Fig. 5c). Of the
crucial to accurately localize the M1 region articles we reviewed, six studies reported the use
during treatment. Currently, motor evoked of a neuro-navigation technique that can detect
potentials (MEPs), the 10–20 electroen- hypermetabolic or hyperactive cortical regions
cephalography system (EEG 10/20 system) and by positron emission tomography (PET) or
neuro-navigation methods are used in clinical functional magnetic resonance imaging (fMRI)
practice to locate M1 targets. [19, 21, 23, 26, 34, 36]. This method should
allow better reproducibility and accuracy
MEP-Based Method regarding the identification of the stimulation
Nineteen of 30 selected studies used the MEP- site and potentially increased efficacy [12].
based method to target M1. The optimal stim-
ulation site, the motor hot spot, could be Stimulation Parameters of Analgesic rTMS
determined according to visual detection of
muscle twitches with this method [22] (Fig. 5a). rTMS paradigms are mainly defined with four
The resting motor threshold (RMT) is defined as stimulation parameters: stimulation frequency,
the minimum stimulator intensity needed to stimulation intensity, number of pulses, and
evoke at least one visible muscle twitch in the number of sessions (Table 2).
extensor hallucis brevis muscle while main-
taining a relaxed position
Stimulation Frequency
[20, 22, 24, 25, 32, 33, 37, 42]. The DLPFC/PMC
Stimulation frequency is the most crucial
location can also be defined with respect to M1
parameter for rTMS therapeutic applications
(5 cm anterior to M1) [29, 30, 49, 50] (Fig. 5a).
[12]. rTMS typically falls into two categories:
MEP recordings are simple and maneuverable
high-frequency rTMS (HF rTMS), with a fre-
and are by far the most widely used method to
quency between 5 and 20 Hz, and low-fre-
locate M1 in clinical rTMS treatment.
quency rTMS (LF rTMS), with a frequency at
1 Hz or less. HF rTMS is commonly considered
EEG 10/20 System Method excitatory, whereas LF rTMS is considered
The EEG 10/20 system is the standard electrode inhibitory [55–58]. Among the 24 rTMS studies,
placement system developed by the Interna- HF rTMS was used in 21 (87.5%), and LF rTMS
tional Brain Mapping Society [51]. It is charac- was used in three (12.5%). Among the 21 HF
terized by the arrangement of electrodes with rTMS studies, 5—10 Hz stimulation was used in
respect to the size and shape of the skull. Elec- 17 studies (81.0%), and 20 Hz stimulation was
trodes are appropriately distributed in the main used in four studies (19.0%).
part of the skull in the standard position
(Fig. 5b). Marker points with the same name can
Stimulation Intensity
be considered to correspond to roughly the
To indicate treatment dosage, the RMT is
same anatomical regions of the brains of dif-
determined at the initial treatment session, and
ferent subjects. In the literature, the stimulating
treatment intensity is titrated from 80 to 120%
electrode is typically placed over C3 or C4 (in
of the RMT depending upon patient tolerance
324 Pain Ther (2021) 10:315–332

[59]. Among the 24 rTMS studies, 11 selected Session Number

90% of the RMT, eight selected 80% of the RMT, Although the duration of the effects of a single
and five selected at least 100% of the RMT as the rTMS is short-lasting, longer-lasting subsequent
final intensity. effects can be achieved by using longer periods
of stimulation or multiple rTMS sessions [63].
Pulse Number Researchers tend to use more than a single rTMS
According to the different number of pulses, session, since the most robust analgesic effects
TMS is usually divided into single-pulse TMS were found to occur 2–4 days after an rTMS
(sTMS), paired-pulse TMS (pTMS), and rTMS session, and the analgesic effect remained for a
[60–62]. rTMS is mostly used for analgesia [12]. fortnight after the last treatment, but this ben-
Of the 24 rTMS studies in this review, 18 studies eficial effect generally lasted less than 1 month
(75%) used between 1000 and 2000 pulses. [12, 26].
Three studies (12.5%) used 500–600 pulses, and
three studies (12.5%) used 2500–3000 pulses.

Fig. 5 Common methods for targeting brain regions in properly distributed in the main part of the skull in a
NIBS. a MEP-based method was used to target M1 of the standard position (left). Schematic diagram of standard
patient (left). In detail, the coil is placed over the electrode placement for EEG 10/20 system (right). The
contralateral hemisphere in the area corresponding to the position of the C3/C4 electrode is assumed to correspond
M1, and the optimal stimulation site is found by moving to the M1 region, while the DLPFC region is targeted by
the coil over the scalp to the site that evokes the largest placing the stimulating electrode on the scalp at F3/F4.
MEP amplitude in the resting state of target muscle (the Cz = vertex. c Schematic diagram of using neuro-naviga-
orange circle represents the M1 area of the brain, and the tion to target brain regions. The patient lies on the bed in
red spot represents the optimal stimulation site), and then a relaxed posture, and neuro-navigation is used to define
along the central axis direction forward 5 cm is considered the target of magnetic stimulation which is the M1 in its
DLPFC region (the black spot) (right). b Picture of subdivision representing the hand
electrode cap on patient’s head, in which the electrodes are
Pain Ther (2021) 10:315–332 325

Table 2 Summary of the parameters of rTMS on NP patients

rTMS Parameters
Ref Stimulation Stimulation Pulse Session
Frequency (Hz) Intensity (% RMT) Number (n) Number (n)
1. Galhardonl R et al., 2019 [36] 10 90 1500 5

2. Ander-Obadia N et al., 2018 [37] 10 90 2000 2

3. Benjamin P et al., 2018 [19] 20 80 1600 4

4. Nizard J et al., 2018 [35] 1 110 1200 6

5. KOHúTOVá B et al., 2017 [31] 5 80 600 1

6. Shimizu T et al., 2017 [20] 5 90 500 5

7. Ayache SS et al., 2016 [26] 10 90 3000 3

8. Malavera A et al., 2016 [14] 10 90 1200 10

9. Hodaj H et al., 2015 [42] 10 80 2000 7

10. Pommier B et al., 2015 [21] 20 80 1600 4

11. Khedr EM et al., 2015 [32] 20 80 2000 10

12. Lindholm P et al., 2015 [34] 10 90 1000 5

13. Nizrad J et al., 2015 [38] 10 80 2000 5

14. Hosomi K et al., 2013 [22] 5 90 1500 10

15. Onesti E et al., 2013 [28] 20 100 1500 5

16. JETTé F et al., 2013 [33] 10 90 2000 1

17. Lefaucheur JP et al., 2012 [23] 10 90 2000 3

18. Lefaucheur JP et al., 2011 [24] 10 90 2000 2

19. Sampson SM et al., 2011 [29] 1 110 1600 15

20. Di Rollo A et al., 2011 [45] 1 80 600 10

21. Lefaucheur JP et al., 2010 [27] 10 90 2000 2

22. Picarelli H et al., 2010 [25] 10 100 2500 10

23. De Oliveira RA et al., 2014 [30] 10 120 1250 10

24. Attal N et al., 2016 [39] 10 80 3000 3

Study of ineffective treatment is labeled gray

rTMS repetitive transcranial magnetic stimulation, RMT resting motor threshold

Stimulation Parameters of Analgesic tDCS polarize the neurons close to the electrode,
thereby increasing neuronal firing. Conversely,
The design of a tDCS protocol particularly a negatively charged electrode (cathode)
requires establishing three parameters: current decreases the excitability of the cortex and
intensity, session duration, and number of ses- induces hyperpolarization of the neurons
sions (Table 3). [64, 65]. The tDCS used in the studies summa-
rized in the present review achieved an anal-
Current Intensity gesic effect when the current intensity was 1 or
The stimulation form of tDCS includes anode 2 mA (Table 3).
tDCS (atDCS) and cathode tDCS (ctDCS). When
a positively charged electrode (anode) is placed Session Duration
on the surface of the skull, a portion of the Session duration is the total amount of time the
current is thought to enter the brain and patient spends in treatment [39, 66]. The tDCS
used in the present review could achieve
326 Pain Ther (2021) 10:315–332

Table 3 Summary of the parameters of tDCS on NP patients

tDCS Parameters
Ref Current Session Session
Intensity (mA) Duration (min) Number (n)
1. Attal N et al., 2016 [39] 2 30 3

2. Houde F et al., 2020 [44] 2 25 5

3. Bolognini N et al., 2013 [16] 2 15 5

4. Soler MD et al., 2010 [40] 2 20 10

5. Antal A et al., 2010 [43] 1 20 5

6. Jensen MP et al., 2013 [41] 2 20 1

Study of ineffective treatment is labeled gray

tDCS transcranial direct current stimulation

analgesic effects when the session duration was Similar to rTMS, the analgesic effects of tDCS
20–30 min (Table 3). may be due to the modulation of the distal
neural structures of NP, including sensory-dis-
Session Number criminative, cognitive, or emotional aspects of
Session repetition timing may reflect the non- NP [71]. Imaging studies have shown that tDCS
linear relationship between tDCS settings and additionally affects structures involved in
the biological effects produced [13, 67]. The affective, cognitive, and emotional aspects of
tDCS used in the present review achieved an pain, such as the cingulate and orbitofrontal
analgesic effect over 5–10 sessions (Table 3). cortices [72, 73].

Potential Analgesic Mechanisms of NIBS Activation of the Endogenous Opioid System

Unfortunately, the mechanism underlying the However, the mechanisms of NIBS must be
analgesic treatment effect of NIBS is unclear. multiple and complex, related to the regulation
The following three hypotheses have been of neural excitability and synaptic plasticity,
described in the literature in this review. and involve various neurotransmitter systems,
such as endogenous opioids, glutamate,
Wide Brain Regulation Beyond M1 gamma-aminobutyric acid (GABA), and/or
Bearing the anatomical evidence of structural dopamine [74, 75]. rTMS of the DLPFC can also
and functional connections in mind, the wide- cause endogenous opioidergic pain relief when
spread impact of neuromodulation of M1 combined with opioid activity [59]. Studies
stimulation to treat NP can be explained suggest that tDCS in combination with medi-
[64, 68, 69]. In fact, the effects of rTMS are not cation-assisted treatment could be an effective
only exerted in the area of stimulation, but also strategy in reducing cravings for opioid use
spread over the associated cortical, subcortical, [13, 52, 76].
and spinal structures. In addition, rTMS on the
M1 can modulate the activity of cortical and Promotion of GABA Release
subcortical regions such as the contralateral M1, Cortical inhibition is the neurophysiological
thalamus, ACC, somatosensory cortex, insula, process by which GABA-inhibited interneurons
and cerebellum. Notably, M1-rTMS consistently selectively attenuate the activity of cortical
interferes with activity in brain areas associated pyramidal neurons, and impairment of this
with painful emotions, including the ACC and cortical inhibition is a mechanism associated
insula, explaining the effects of M1 stimulation with NP [63, 77, 78]. HF rTMS produces excita-
on the emotional aspect of pain [25, 70]. tory effects, and is thought to enhance synapse
Pain Ther (2021) 10:315–332 327

plasticity by inducing long-term potentiation current intensity of 2 mA, a session duration of

(LTP). In contrast, LF rTMS generates inhibitory 20–30 min, and 5–10 sessions.
effects, presumably through long-term depres- A limitation of this review is that when we
sion (LTD) [23, 79, 80]. rTMS may induce mul- summarized the analgesic effect of NIBS, we
tiple alterations related to LTD and LTP [63]. focused on NP and further divided NP into TNP
Magnetic resonance spectroscopy (MRS) studies and SNP. However, we did not involve other
have shown that atDCS reduces local concen- types of pain, so it is inevitable that there are
trations of the inhibitory neurotransmitter some omissions in the summary of the param-
GABA, whereas ctDCS reduces excitatory gluta- eters of the analgesic treatment effects of NIBS.
mate levels [81–83]. The placebo effect of NIBS can be studied by
two means: firstly, the clinicians have posi-
tioned an active coil over an area distant from
DISCUSSION the targeted stimulation area; alternatively, the
coil positioned as the targeted stimulation area
NP resulting from lesions or diseases of the has been adjusted to an angle of 45° or 90° rel-
nervous system represents an important medi- ative to the scalp has from the tangential style
cal challenge. Our systematic review highlights [1]. In the present review, 15 reports from a total
the analgesic effects of NIBS in patients with NP. of 24 rTMS reports as well as four reports from
It is important to note that NIBS is a noninva- total six tDCS reports have provided the obser-
sive neuromodulation technique that, although vations and analysis of the placebo effect. In 15
generally well tolerated, warrants special safety rTMS studies, four have reported that pain
considerations for side effects in patient popu- scores did not change significantly by sham
lations, such as local burning, tinnitus, head- rTMS, which has indicated the lack of placebo
ache, disturbance of grafts, and even induction effect of rTMS [24, 26, 28, 37]. In four tDCS
of seizures. Therefore, the aim of this paper is to studies, two have reported that pain scores did
summarize the analgesic effects of NIBS on dif- not change significantly by sham treatment,
ferent NPs in order to reduce the occurrence of which has indicated the lack of placebo effect of
adverse effects. tDCS [16, 40]. Furthermore, all other 11 rTMS
In this manuscript, instead of using the reports and two tDCS reports have shown that
classic central and peripheral classifications, we the pain scores of the subjects could be signifi-
classified the most common (large number of cantly reduced by active rTMS or tDCS, but not
cases) types of NP as typical NP (TNP), including by sham rTMS or sham tDCS.
diabetic neuropathy, stroke, spinal cord injury, There are few data related to the long-term
and nerve injury. The remaining clinically rare benefit of tDCS as a useful tool to alleviate
types are classified as special NP (SNP), such as neuropathic pain. Dalla Volta et al. have
facial pain, phantom limb pain, cancer pain, observed that 3 months after the last tDCS
and other types of pain. We hope that this new stimulation, the patients with drug-resistant
classification will provide additional benefit in migrainous could still obtain a reduction of
terms of understanding and treating NP. This 50% of pain scores [84]. However, some reports
systematic review reveals that, in general, the have shown that there is no long-term analgesic
optimal therapeutic parameters for rTMS/tDCS effect of tDCS on chronic migraine [85] or lung
and the treatment of NP should allow the cancer pain [86], while the long-term effect of
design of optimal treatments for individual rTMS on pain relief has been shown in a
patients. 6-month study of rTMS treatment in patients
Based on the results of the review, the stim- with facial pain [42] or with nerve injury
ulation parameters of rTMS that best induce an induced NP [35]. We have also noticed that the
analgesic effect are a stimulation frequency of active rTMS could significantly reduce pain
10—20 Hz, a stimulation intensity of 80–120% intensity with the time course of 25 weeks [79]
of RMT, 1000–2000 pulses, and 5–10 sessions, or even 2.8 years [21].
and the most effective parameters of tDCS are a
328 Pain Ther (2021) 10:315–332

Given that the scientific evidence is still Compliance with Ethics Guidelines. This
limited, there is a need for multicenter coordi- article is based on previously conducted studies
nation, more randomized controlled studies and does not contain any new studies with
and the integration of big data to deepen the human participants or animals performed by
current understanding of the analgesic mecha- any of the authors. Written informed consent
nisms of rTMS and tDCS. was obtained for the use of the two patients’
photographs in this publication.

Data Availability. The datasets generated

ACKNOWLEDGEMENTS
during and/or analyzed during the current
study are available from the corresponding
We thank the participants of the study.
author on reasonable request.

Funding. This study and the journal’s Rapid Open Access. This article is licensed under a
Service Fee was supported by the International Creative Commons Attribution-Non-
Science and Technology Cooperation Program Commercial 4.0 International License, which
of Shaanxi Province to Prof. Hua Yuan permits any non-commercial use, sharing,
(2020KW-050), and the Army innovation Pro- adaptation, distribution and reproduction in
ject to Prof. Hua Yuan (16CXZ022). Grants from any medium or format, as long as you give
the Open Project 2018KA01 from State Key appropriate credit to the original author(s) and
Laboratory of Military Stomatology to Prof. Ya- the source, provide a link to the Creative
Yun Wang (2018KA01), and the Key R&D Pro- Commons licence, and indicate if changes were
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Authorship Contributions. Kun-Long Zhang:
creativecommons.org/licenses/by-nc/4.0/.
Conceptualization, Writing- Original draft
preparation. Hua Yuan: Conceptualization,
Writing- Original draft preparation. Fei-Fei Wu:
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