Effectiveness of transcranial magnetic stimulation in the management of oncological and non-oncological neuropathic pain. A systematic review

doi:10.21203/rs.3.rs-1416786/v1

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Effectiveness of transcranial magnetic stimulation in the management of oncological and non-oncological neuropathic pain. A systematic review

https://doi.org/10.21203/rs.3.rs-1416786/v1

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Purpose: Transcranial Magnetic Stimulation (rTMS) emerges as an innovative alternative for the management of neuropathic pain, rTMS is a non-invasive brain stimulation technique which induces electrical currents in the nervous tissue of the cortex. The objective of this study was to evaluate the effectiveness of rTMS in the management of oncological and non- oncological neuropathic pain.

Methods: The search was performed in CENTRAL, MEDLINE, Embase, PsycINFO, SCOPUS and LILACS. Inclusion criteria were 1) population: Male and female between 18 and 85 years with oncologic and non-oncologic neuropathic pain; 2) intervention: Treated with Transcranial magnetic stimulation; 3) comparison: Inactive control groups, and parallel active interventions; and 4) outcome: Primary outcome was modulation of pain. Secondary outcomes were quality of life and adverse effects. Risk of bias and quality of study reporting were also assessed.

Results: The search found 1116 articles, with 18 articles meeting the PICO criteria. 9 ECAS and 9 observational studies. The total sample was 707 patients, the number of sessions ranges from a single session to 15 sessions, with an average of 3.5 sessions. Follow-up was variable. The Follow-up vary from 7 to 311.8 days, with an average of 45 days. Pain reduction was obtained in the 18 studies.

Conclusion: rTMS may be and effective therapeutic option to treat neuropathic pain. We found moderate quality of evidence for pain modulation; for quality of life the results are uncertain to determine changes, due to very low evidence. Additional research effort is needed to reduce bias and improve quality.

Neurophatic pain

Transcranial magnetic stimulation

Cancer pain

Neuropathic pain includes any type of injury or primary dysfunction that affects both the peripheral (PNS) and central (CNS) nervous system (1,2). Etiologically it can occur for various causes: trauma, ischemia or hemorrhage, inflammation, neurotoxicity, neurodegeneration, metabolic, vitamin deficiency, or cancer (3,4).

The estimated prevalence of neuropathic pain in the general population is between 7 and 10% (5). This may vary according to the criteria for diagnosis, the methods of evaluation, and the characteristics of the patient (6).

Furthermore, pain is a very common problem in cancer patients (7,8), more than 30% of cancer patients experience neuropathic pain (9); the third part is caused by chemotherapy and radiotherapy induced neuropathy, with an important impact on quality of life (10,11).

Pain is a complex symptom of great importance in daily clinical practice, requiring multidimensional treatment (12). Neuropathic pain affects physical, psychological, and emotional conditions, causing depression and anxiety (13–15). Currently, the pharmacological treatment options range from medication with nervous system modulators, anticonvulsants, tricyclic antidepressants, and opioids. Other treatment alternatives include: Home remedies, physiotherapy, alternative medicine, surgery, and nerve blocks (2,4,16–18).

In the search for therapeutic options for patients with chronic pain management, Transcranial Magnetic Stimulation Therapy (rTMS) emerges as an innovative alternative, which is a non-invasive, safe, and painless neurophysiological technique which induce electrical currents in the nervous tissue of the cortex (19). The analgesic effect begins with stimulation of the primary motor cortex (M1) (20).

rTMS is a novel technique in the field of physiotherapy which constitutes a therapeutic reality in rehabilitation, helping the brain in its ability to readapt neural circuits (21–23). Thus, in the clinical practice guidelines developed by Cruccu, G,.2016 (5) and Lefaucheur, J. P,.2020 (24), multiple studies have analyzed rTMS application, in different pathological conditions, such as fibromyalgia, radicular pain, post-herpetic neuropathy, phantom pain due to amputation, complex regional pain syndrome, among others (25–28).

The Physiotherapist, as part of the interdisciplinary group in the treatment of neuropathic pain, must promote high quality and comprehensive health services. For this reason, the objective of this study was to evaluate the effectiveness of transcranial magnetic stimulation in the management of oncological and non- oncological neuropathic pain.

This systematic review was conducted according to the recommendations published by Cochrane (29) and reported in line with the PRISMA statement (30). The research protocol was registered in PROSPERO (registration number: CRD42021236999).

Selection criteria

The selection criteria was defined according to the PICOS acronym (i.e., population, intervention, comparison, outcomes, and study design).Based on the guidance from the Cochrane EPOC group (the Effective Practice and Organization of Care) the following study designs were included: Randomized controlled clinical trials (RCTs), non-randomized controlled clinical trials, and interrupted time series (31).

Types of participants

Male and female between 18 and 85 years with oncologic and non-oncologic neuropathic pain.

Type of Intervention

Treated with Transcranial magnetic stimulation

Settings

We limited neither setting nor delivery format for the interventions.

Time: Studies that evaluated at least one session, in which the outcome of interest was measured or previously informed through validated instruments.

Comparison

Inactive control groups (e.g., no intervention) as well as parallel active interventions, such as TENS and direct transcranial stimulation.

Outcome measures

Primary outcomes

Modulations of pain measured in validated scales

Secondary outcomes

Quality of life
Adverse effects of either receiving the intervention or related to false-positive results of any symptom

Exclusion criteria

Pain characteristics which do not answer the PICOS´s question or do not studied neuropathic pain.

Search Methods

The search was carried out between the years 2011–2021, these dates were selected due to the increased number of articles studying the effect of the transcranial magnetic intervention for neuropathic pain recently (32). Language restriction shall not apply. The search terms are detailed in Appendix 1. The following electronic database search sources were consulted: The Cochrane Central Register of Controlled Trial (CENTRAL), MEDLINE, EMBASE, PsycINFO, SCOPUS and LILACS. For clinical trial records the search portal of the international platform of clinical trial Records of the WHO (ICTRP) (http://apps.who.int/trialsearch/), the National Institute of Health clinical trials database (http://clinicaltrials.gov) and the International Register of Controlled Trials (http://www.controlled-trials.com) were consulted. To identify additional studies, a manual search of the bibliographies of all included studies was performed. In addition, we searched on OpenSIGLE (www.opengrey.eu). When additional information was required, the corresponding authors were contacted. (See appendix 2).

Data collection and analysis

Selection of studies

The references identified in the literature searches were exported to the reference manager Mendeley (https://www.mendeley.com) and software for Rayyan systematic reviews (https://rayyan.qcri.org), to later carried out the elimination of duplicates and evaluation of the titles and summaries by the four independent evaluators CLM, ICAB, SPBB, and MGVM. The next step was to recover the full text of the studies that met the inclusion criteria. The discrepancies between reviewers were resolved by discussion or with the participation of another evaluator (SGT or DVM).

The studies that were excluded during the evaluation process of the full text were grouped in a list that was referred to as the "Characteristics of the excluded studies" and the reasons for exclusion were reported (Fig. 1.)

Data extraction

We followed the data extraction format suggested by Cochrane (29) to gather relevant information for each study, including characteristics of participants, characteristics of the interventions, comparisons, study designs, and results, and evaluator (ICAB) extracted data from included studies and a second evaluator (CLM) verified the accuracy of the information. Any disagreement in consensus was resolved, by consulting a third researcher.

Assessment of the risk of bias

Two independent reviewers (SPPB and CLM) who were blinded to the concepts of the other assessed the risk of bias in the included studies. The risk of bias of RCTs was systematically appraised using the Cochrane risk of bias tool (33). Non-randomized uncontrolled trials were appraised with the Quality Assessment Tool for Before-After Studies with No Control Group of the National Heart, Lung, And Blood Institute (34) and the checklist for quasi-experimental studies (non-randomized Experimental Studies of Johana Brinks Institute). Any disagreement was resolved by consensus meetings or by consulting a third reviewer when needed.

Data Synthesis

Due to both the limited amount of data and the heterogeneity in the included studies, we decided to provide a narrative synthesis of the main findings. No meta-analysis was undertaken.

Quality of evidence

Two independent reviewers (SPBB, CLM) used the GRADE approach (Grading of Recommendations, assessment, development, and evaluation) to evaluate the quality of the evidence (35). This can be reduced by the following factors (36): limitations in the design and implementation of the study (risk of bias), inconsistency of results, indirectness of evidence, imprecision and publication bias. Summary of findings table was generated in GRADEpro software (37).

Main findings.

The search found 1116 articles (see Fig. 1), of these 1701 in Medline, 5 in Lilacs, 270 in Cochrane, 138 in Embase, 34 in PsycINFO, and 2 in grey literature; After deleting the duplicates 1055 abstracts were read to identify compliance with the selection criteria; 960 were excluded, leaving 95 to which the text was completely read; in this last revision 65 were excluded leaving 30, of which, by making a judicious review of the PICO, 12 were excluded which did not contemplate the approach or type of the study, or included different types of pain. In the end, 18 articles complied with the PICO proposed. Those articles are summarized on Table 1.

Table 1

Summary of interventions and results from included studies
Study	N	Intervention	Result	Quality of life
Khedr et al., 2015	n = 34 oncologic neuropathic pain	10 sessions, 5/week. 20 Hz, 10 sec, 80% intensity, 10 sessions Follow-up two weeks	Pain reduction	N/A
Quesada et al., 2020	N = 42 central neuropathic pain	Four sessions, 20 consecutive trains of 80 pulses at 20 Hz, at 80% of the engine threshold, the interval of 84 s, during a session of 27 minutes.	Pain reduction	Remained unchanged.
Abdelkader et al., 2019	N = 20 diabetic neuropathy	5 sessions of 40 minutes, 15 consecutive trains (2 s duration) of 50 stimuli at 10 Hz, at 100% of the engine threshold, intervals between trains of 30 s were delivered.	Significant pain reduction	N/A
Ahmed et al., 2020	N = 30 diabetic neuropathy	5 sessions/20 Hz or sham/80% RMT/2000 pulses/M1 Follow-up 5days, 1, and 2 months	Significant pain reduction	N/A
Attal et al., 2016	N = 36 lumbar neuropathic radicular pain	3 sessions, 3 consecutive days, 3000 pulses (30 trains of 10 seconds each, with an interval between trains of 20 seconds) delivered at a frequency of 10 Hz.	Pain reduction	N/A
Hosomi et al., 2020	N = 144 neuropathic pain from different locations	An active rTMS session involved 10 trains at 90% RMT (50 pulses/train at 5 Hz; the interval between trains, 50 seconds)	Pain reduction	Remained unchanged
Hosomi et al., 2013	N = 70 neuropathic pain from different locations	1 session/5 Hz/90% RMT/500 pulses/M1 Follow-up 17 days	Pain reduction	N/A
Kim et al., 2020	N = 30 central neuropathic pain	A daily rTMS session was held for 5 days. 3 pulses (60 ms) at 50 Hz and a 5 Hz TBS train of last 2 sec, intervals of 10 seconds for 200 seconds (600 stimuli in total), with an 80% intensity	Significant pain reduction	N/A
Cervigni et al., 2018	N = 13 painful bladder syndrome and interstitial cystitis	The sessions of 30 consecutive trains of 50 stimuli delivered at 20 Hz at 110% of the RMT	Significant pain reduction	Improvement
Goto et al., 2020	N = 11 chemotherapy-induced neuropathy	20 Hz, 10 s, 10 trains with 80% intensity. Four sessions	Pain reduction	N/A
Lindholm et al., 2015	N = 16 orofacial pain	1 session/10Hz or simulation /90% RMT/1000 pulses/contralateral S1-M1 or S2 right. Four weeks Follow-up	Significant pain reduction	Improvement
Pommier et al., 2016	N = 40 central neuropathic pain	Four sessions, 20Hz, 20 consecutive trains of 80 stimuli at 80% of the engine threshold, intervals between trains of 84 s, session of 26 minutes. Follow-up average of 311.8 days.	Pain reduction	N/A
(Ayache et al., 2016)	N = 66 neuropathic pain from various causes and locations	A single session of 10 Hz-rTMS M1	Significant pain reduction	N/A
(Hodaj et al., 2020)	N = 57 neuropathic pain from different locations	10 daily sessions for 2 weeks and then 2 sessions in 1 week followed by 3 weekly sessions, 2 weekly sessions, and 5 monthly sessions / 10 Hz / 80% / 2000 pulses in 20 minutes. Follow-up 0.5, 1, 3 and 6 months	Significant pain reduction	Significant improvement
Lawson McLean et al., 2018)	N = 48 neuropathic pain from various sources	10 Hz- rTMS on M1	Significant pain reduction	N/A
Lefaucheur et al., 2012	N = 14 neuropathic pain from different locations	1 session/10 Hz/90% AMT/2000 pulses/M1 preceded or not by iTBS or cTBS/80% AMT/600 pulses/M1 One week Follow-up	Pain reduction	N/A
Nurmikko et al., 2016	N = 27 neuropathic pain of different origins	10 Hz, 80% RMT, 3000 pulses, 3 sessions	Pain reduction	N/A
Sampson et al., 2011	N = 9 neuropathic pain from different locations	15 sessions/1 Hz/110% RMT/1600 pulses/ correct DLPFC Follow-up 1, 3 weeks and at 3 months	Pain reduction	N/A
RMT: Resting motor threshold. AMT: Active motor threshold. rTMS: Repetitive transcraneal magnetic stimulation. cTBS: Continuous Theta burst stimulation. iTBs: Intermittent Theta burst stimulation. DLPFC: dorsolateral prefrontal cortex.

Participant characteristics

We included 18 articles: 9 ECAS and 9 observational studies. The total sample of the studies was 707 patients, with 312 (44.14%) women and 395 (55.86%) men. The average age was 52 years old.

Intervention

All studies used rTMT in their treatment, the number of sessions vary from a single session to 15 sessions, with an average of 3.5 sessions. Follow-up was variable ranging from 7 to 311.8 days, with an average of 45 days. Pain reductions were obtained in the 18 studies.

Excluded studies

The main reasons for exclusion were different intervention, pain nature and type of study. Appendix 3.

Primary outcomes

Pain Modulation

From the 18 articles included 9 were ECAS (38–46), with a total population of 419 patients.

The article of Khedr et al., (2015) (38) , included 34 patients with a diagnosis of chemotherapy-induced neuropathy, rTMS treatment was performed in 10 daily sessions, 5 days a week. Pain assessment was performed before and after the first, fifth, and 10th session and then 15 days and one month later. Changes in the verbal descriptor scale (VDS), and visual analog scale (VAS) were significant in the intervention group, particularly at the end of treatment, 49.1% VDS and 36.7% VAS and at 15 days of follow-up 45.6% VDS and 35.5% VAS.

The study of Quesada et al., (2020) (39) included 42 adults with central pain, divided into active and simulated phases. Each phase included 4 sessions and an 8-week washout between phases. The pain was assessed with VAS assessed after each rTMS session and at the end of the phase. There was a mean difference of 20.79% R (95% CI) between the active and sham phases. 23 patients (54%) and 15 patients (35%) achieved pain relief of >30% or >50%, respectively.

Two articles included adults with diabetic neuropathy (40,41). The results were evaluated with VAS in both studies. Abdelkader et al., (2019) (40) reported a significant mean VAS reduction for insulin-dependent patients (5.10 ± 2.6 mm; p = 0.011) and non-insulin-dependent patients (4.0 ± 1.7 mm; p = 0.005). Ahmed et al., (2020) (41) found significant decreases (P<0.05) in pain severity after rTMS and after TENS intervention.

The article of Attal et al., (2016) (42), included a population of 36 patients, 24 for active stimulation and 12 for sham group. The treatment protocol included two blocks separated by an interval of three weeks. Each block consisted of three sessions of rTMS or tDCS (transcranial direct stimulation) on three consecutive days (V1, V2, V3). Treatment effects were assessed with Numerical Rating Scale (NRS) immediately before stimulation in V1, after stimulation in V2 and V3 and five days after the last session. The study concluded that active rTMS was superior to tDCS and simulation in pain intensity (F = 2.89; p = 0.023). rTMS reduced cold pain thresholds (p = 0.04) and its effect on cold pain was correlated with analgesic efficacy (p = 0.006).

The study by Hosomi et al., (2020) (44), included 144 patients with pain from different locations. 70 patients for active treatment and 67 patients for sham rTMS. Patients received 5 daily sessions of active or sham rTMS. In addition, responders whose VAS decreased an average of 10 mm or more with daily rTMS could join a continuous open-ended trial to test active rTMS administered at least once a week for 4 weeks. The VAS was recorded before and after each intervention, the decrease in the mean VAS was 8.0 (SD, 12.1) in the active stimulation group and 9.2 (SD 13.6) in the simulated group.

The article of Hosomi et al., (2013) (45), included 70 patients with neuropathic pain from different locations, 34 in group A and 36 in group B. As for the treatment, a session of rTMS was applied daily for 10 consecutive days. Pain intensity was assessed daily in each patient using a visual analog scale (VAS; 0-100 scale). In the results, the mean rates of reduction in VAS (95% CI) averaged in real and simulated rTMS were 6.51% (3.68–9.34) vs 2.44% (0.98–5.62) just after stimulation, and 3.38% (1.13–5.62) vs 0.66% (2.74–1.43) 60 min after.

Kim et al., (2020) (46), included 30 patients who presented a central neuropathic pain, 15 patients in group A and 15 in group B. A daily rTMS session was held for 5 days. Patients were evaluated with the NRS of 11-point scale. There was a significant reduction in NRS of the real group with a difference of 15.20±7.46.

In the article of Cervigni et al., (2018)(43), 13 patients with neuropathic pain caused by painful bladder syndrome/interstitial cystitis were chosen. The first group of patients received rTMS-real treatment for five consecutive days followed, by a washout period of 6 weeks, for the simulated treatment of rTMS; the second group received the same treatments in reversed order. The scales used to assess pain were VAS, Functional Neuropathic Pelvic Pain syndrome (FPPS), Neuropathic Pain Symptom Inventory, McGill Questionnaire, and Central Sensitization Inventory LUTS Urinary. In the actual stimulation phase, it obtained a significant overall reduction for VAS (F [5.45] = 5200, P = 0.001).

Of the 18 studies, 9 quasi-experimental studies were found (47–55) with a total population of 288 patients.

Goto et al,. (2020) (47), included 11 adults with oncological diagnosis and chemotherapy-induced neuropathy, who underwent 4 sessions of rTMS. Pain was assessed at baseline, pre-intervention, and post-intervention. P-VAS scores decreased significantly in pre-stimulation (mean 55.3) and after stimulation (mean 46.8).

Pommier et al., (2016) (49) included 40 adults with neuropathic pain of central origin who underwent 4 sessions separated from each other by an interval of 3-4 weeks. The evaluation was carried out after 4 sessions. In the 31 patients who responded, the average number of sessions per patient was 11, the average follow-up was 311.8 days, the average interval between sessions was 28.4 days. The average percentage of pain relief (Global %R) in the responder's group was 41%. The mean VAS score before rTMS was 6.35 vs 6.16 after four sessions.

The study of Lindholm et al., (2015) (48), had 16 adults with orofacial pain. All participants received 2 active rTMS treatments and 1 sham treatment (placebo). The 3 treatments were separated from each other by 4 weeks. NRS was assessed at baseline and after each rTMS session. Brief Pain Inventory (BPI) was evaluated at baseline, 3-5 days after treatment and 1 month after. Pain intensity (NRS) was lowest on the third day after S2 stimulation (MS: 3.8, SE: 0.6) in comparison with S1/M1 stimulation (MS: 5.4, SE: 0.6; P 5 0.0071) or simulated (MS: 5.3, SE: 0.6; P 5 0.0187). These results remain after 1 month.

Ayache et al., (2016)(50), included 66 patients with neuropathic pain of different causes and locations, who were evaluated for the analgesic effect in a single session. This study compared analgesia induced by stimulation of pain location without hand motor hot spot (hMHS) consideration, versus primary motor cortex (M1). The analgesic effect was assessed with VAS, finding that the percentage of pain reduction during the week (PPRweek) and for the days 2 and 3 (PPRd2d3) showed a significant difference during the hMHS-targeted procedure and the M1 compared to the sham procedure (p<0.05 and p<0.001, respectively).

The study of Hodaj et al., (2020) (51) had 57 pain patients from different locations. The treatment consisted of one session per day for five days for two consecutive weeks (weeks 1 and 2), then 2 sessions in the following week (week 3) for a total of 12 sessions. Maintenance therapy was conducted, consisting of a rTMS session at week 4 and then bi-monthly sessions over the next five months, for a total of 11 sessions.

Lawson McLean et al., (2018)(52), included 48 patients with atypical facial pain, rTMS treatment was performed daily for a total of nine sessions. Pain intensity was documented according to the visual analog scale.

In the study of Lefaucheur et al., (2012) (53), 14 patients with different pain locations where included. The patients underwent 3 sessions separated by four weeks. The pain was assessed with VAS for 1 week, before the first rTMS session and after each rTMS session. The mean pain score reduction score was 41% when combined with iTBS (intermittent theta-burst stimulation) and 31% compared to cTBS (continuous theta-burst stimulation).

Sampson et al., (2011) (55) performed 15 rTMS sessions on 9 patients with pain from different locations, (5 days a week for 3 weeks). p-VAS was evaluated before and after all rTMS treatments and monthly for 3 months. In the results, three subjects had a 50% decrease in pain ratings upon completion of rTMS treatments, and 1 subject responded more slowly with a 50% improvement in pain at the end of the 3-month follow-up.

The study of Nurmikko et al., (2016) (54) included 27 patients with pain from different parts of the body. Divided into 3 groups: Pharmacological treatment, rTMS, and the control group. Treatment was designed by applying 3 cycles of 5 sessions of rTMS 3-5 times per week. Patients rated their average pain every 24 hours with the NRS, and before and after 5 sessions patients completed the Brief Pain Inventory (BPI). The results showed that rTMS provided pain relief and increased the total rate of responders by 58%.

Secondary outcomes

Quality of life

In the search, we found 5 articles that evaluate the quality of life in their results. The sample amounts to 272 patients (39,43,44,48,51).

In the article of Cervigni et al., (2018) (43), they described a significant overall effect on the SF-36 sub-score related to physical pain, in the actual stimulation phase (F [5.50] = 2636, P = 0.034) and for the emotional state-related sub-score (F [5.50] = 3096, P = 0.016).

In the study of Hosomi et al., (2020)(44), the EQ-5D-5L for quality of life was recorded after each intervention, on the 1st day, after the intervention on the 5th day, and the 4th week. None of the outcomes for quality of life were significantly different between groups.

Hodaj et al., (2020) (51) used Sf-36 and RAND 36 to assess quality of life. A significant improvement for physical and mental component summaries and scores was observed in the results.

In the study by Quesada et al., (2020) (39) quality of life was assessed with EuroQol (EQ-5D), it was applied at the beginning and end of each phase. In the results, the EQ-5D remained unchanged in both the active and simulated phases.

Lindholm et al., (2015) (48) included 16 adults with orofacial pain, quality of life was assessed by NePIQoL and SF-36 at baseline and 1 month later, finding a small reduction in total NePIQol score 1 month after S2 stimulation (S: 79.8, SE: 5.7) compared to baseline (ES: 86.6, SE: 5.7; P50.0031).

Adverse effects

Of the 18 articles included for this systematic review, three (16.66%) of them (38,41,52) do not mention in their content the adverse effects of transcranial magnetic therapy, two of them (11.11%) (42,55) mentioned that these effects are observed and measured, without describing their conclusions. Three of them (16.66%) (43,45,54) mentioned adverse effects classified as mild, among them headache, pain in the extremity, dizziness and drowsiness, being these the most noted. However, ten of the articles (55.55%) (39,40,44,46–51,53) mentioned not having found severe adverse effects in their protocols.

Risk of Bias

Nine of the eighteen studies (38–46) were evaluated with the Cochrane risk-of-bias tool for randomized trials, in summary the studies showed a low risk of selection bias but high risk of performance and detection bias due to the lack of blinding of participants, personnel and outcome assessors. (Figure 2).

The studies with other methodology (47–55) were evaluated with JBI Critical Appraisal Checklist for quasi-experimental studies from the Faculty of Health and Medical Sciences at the University of Adelaide, South Australia, it can be seen that 7 of the 9 articles fulfilled more than 50% of the checklist items. (Table 2.)

Table 2

JBI Critical appraisal checklist for quasi-experimental studies
ITEM	Yes	No	Unclear
1. Is it clear in the study what is the ‘cause’ and what is the ‘effect’ (i.e. there is no confusion about which variable comes first)?	8	0	1
2. Were the participants included in any comparisons similar?	7	2	0
3. Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?	8	1	0
4. Was there a control group?	7	2	0
5. Were there multiple measurements of the outcome both pre and post the intervention/exposure?	7	2	0
6. Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analysed?	7	2	0
7. Were the outcomes of participants included in any comparisons measured in the same way?	9	0	0
8. Were outcomes measured in a reliable way?	9	0	0
9. Was appropriate statistical analysis used?	9	0	0

Quality of evidence

We found moderate quality of evidence for the effects of interventions in Pain Modulation. Very low-quality evidence was found about effects on changes of Quality life (See Figure 3).

The use of rTMS brain stimulation to treat neuropathic pain has increased significantly in recent years, followed by rapid growth in related studies (32,56–58). The present systematic review identified 9 randomized trials and 9 observational studies, with only 2 of those articles specific for the oncologic population (38,47).

Pain is a complex symptom of great importance and impact on the well-being of people with different pathologies and is associated with a high economic burden, for this reason, it requires comprehensive and priority care (59,60). Epidemiological surveys have shown that many patients with neuropathic pain do not receive adequate treatment (61). This may be due to a lack of diagnostic precision, insufficient understanding of the pathophysiological mechanisms of pain, and relatively ineffective pharmacological and non-pharmacological treatment options (62,63). Therefore, better approaches and diversification of therapeutic options are still necessary, which allow an effective modulation of pain and a positive impact on quality of life (64).

rTMS is a non-invasive procedure that has been widely recognized as an effective treatment for intractable neuropathic pain from different origins (25,65). Regarding the analgesic effects of rTMS, all the 18 studies included in the systematic review described an improvement in pain rates, however, the average of pain relief was very variable between studies, probably due to a different number of sessions, frequency, origin of pain and follow up. Pommier, et al,. (2016) (49) reported that after three sessions, patients had a 43% chance of experiencing at least 40% of pain relief with a mean duration of 17.8 days. On the other hand, Khedr, et el,. (2015) (38) described that there were no significant effects on the Visual Analogue scale (VAS) after the first session, but these appeared after the fifth session.

Currently, there is not enough clinical evidence to determine the long-term effect of rTMS therapy. From the included studies only one article performed a long follow-up with an average of 381.6 days (49). These authors suggested that patients who had at least a 40% pain relief after three sessions have an 89% chance to experience pain relief at a 1-year follow-up. Some of the articles selected for the systematic review included 2 to 4 weeks of follow-up (38,40,44,45,48). However, longer periods of pain relief were reported by Hodaj et al (2020) (51) who found that the analgesic effect was still present at 5-month follow-up.

Regarding the follow-up in the oncologic population Kehdr et al,. (2015) (38) described that the effect of rTMS lasts at least for 2 weeks after the end of the treatment sessions but are no longer present at a 1-month follow-up. The other article described that regarding the targeted extremity, the dysesthesia and pain visual analog scores significantly decreased at 2 months (47).

Some articles from the systematic review had assessed the variable of depression, which has shown a relation with neuropathic pain (38,42–45,48,51,54)). This variable may be an interesting element to evaluate for future investigations and it can promote a comprehensive assessment of neuropathic pain from all the patient areas.

Finally, there is evidence available on the effectiveness of transcranial magnetic stimulation for neuropathic pain, however, there are several methodological weaknesses due to inconsistency and heterogeneous study design, study population, and outcome measures. Although the sample size of the primary studies is small, they have the optimal information size (OIS), which favors precision in the results. Thus, it is necessary to develop more rigorous and larger studies that can inform, standardize, and improve clinical practice regarding the modulation of neuropathic pain with rTMS.

Based on the results of 18 experimental studies, including 9 randomized control trials and 9 observational articles, the current systematic review suggests that transcranial magnetic stimulation may be and effective therapeutic option to treat oncological and non-oncological neuropathic pain. We found moderate quality of evidence for pain modulation; for quality of life the results are uncertain to determine changes, we found very low evidence. Therefore, we suggest to include transcranial magnetic stimulation into the treatment protocols for oncologic and non-oncologic neuropathic pain. Regarding quality of life we suggest to develop larger studies were the impact of pain modulation in quality of life is measured. Further, well-conducted RCTs including more standardized methodologies, and better-reported interventions are warranted with special emphasis on oncological population.

Funding: This study was funded by Fundación Universitaria María Cano University.

Competing interests: The authors declare that they have no conflicts of interest.

Availability of data and material: Not Applicable

Code availability: Not Applicable

Author contributions: All authors have contributed to the paper. CLM, ICAB, SPBB and MGVM designed the research, completed the literature search, extracted data, completed the study quality assessment, analyzed the results and prepared the manuscript. SGT and DVM were involved in the study extracted data, quality assessment, analysis and interpretation of results and manuscript preparation.

Ethics approval: Ethical approval was not required for this review.

Consent to participate: Consent was not required for this review.

Consent for publication: Consent was not required for this review.

World Health Organization. WHO Normative Guidelines on Pain Management. 2007.
Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis Primer. 2017 Feb 16;3(1):1–19.
Correa-Illanes G. Dolor neuropático, clasificación y estrategias de manejo para médicos generales. Rev Médica Clínica Las Condes. 2014 Mar 1;25:189–99.
Liampas A, Rekatsina M, Vadalouca A, Paladini A, Varrassi G, Zis P. Non-Pharmacological Management of Painful Peripheral Neuropathies: A Systematic Review. Adv Ther. 2020 Oct;37(10):4096–106.
Cruccu G, Truini A. A review of Neuropathic Pain: From Guidelines to Clinical Practice. Pain Ther. 2017 Dec;6(Suppl 1):35–42.
Rincón-Carvajal AM, Olaya- Osorio CA, Martínez-Rojas S, Bernal L. Recomendaciones basadas en la evidencia para el manejo del dolor neuropático (revisión de la literatura). Rev Soc Esp Dolor [Internet]. 2018 [cited 2022 Jan 12];25(6). Available from: https://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1134-80462018000600349
Perruchoud C, Dupoiron D, Papi B, Calabrese A, Brogan SE. Management of Cancer-Related Pain With Intrathecal Drug Delivery: A Systematic Review and Meta-Analysis of Clinical Studies. Neuromodulation J Int Neuromodulation Soc. 2022 Jan 21;S1094-7159(21)06969-5.
Zis P, Paladini A, Piroli A, McHugh PC, Varrassi G, Hadjivassiliou M. Pain as a First Manifestation of Paraneoplastic Neuropathies: A Systematic Review and Meta-Analysis. Pain Ther. 2017 Dec;6(2):143–51.
Bao H, Wu Z, Wang Q, Wang J, Zhang L, Meng L, et al. The efficacy of gabapentin combined with opioids for neuropathic cancer pain: a meta-analysis. Transl Cancer Res. 2021 Feb;10(2):637–44.
Desforges AD, Hebert CM, Spence AL, Reid B, Dhaibar HA, Cruz-Topete D, et al. Treatment and diagnosis of chemotherapy-induced peripheral neuropathy: An update. Biomed Pharmacother Biomedecine Pharmacother. 2022 Jan 29;147:112671.
Yoon SY, Oh J. Neuropathic cancer pain: prevalence, pathophysiology, and management. Korean J Intern Med. 2018 Nov;33(6):1058–69.
Khosravi Shahi P, Castillo Rueda A del, Pérez Manga G. Manejo del dolor oncológico. An Med Interna. 2007 Nov;24(11):554–7.
Girach A, Julian TH, Varrassi G, Paladini A, Vadalouka A, Zis P. Quality of Life in Painful Peripheral Neuropathies: A Systematic Review. Pain Res Manag. 2019;2019:2091960.
Aamir A, Girach A, Sarrigiannis PG, Hadjivassiliou M, Paladini A, Varrassi G, et al. Repetitive Magnetic Stimulation for the Management of Peripheral Neuropathic Pain: A Systematic Review. Adv Ther. 2020 Mar;37(3):998–1012.
Guerrero A, Gómez M. VIII Estudio Nacional de Dolor 2014: Prevalencia del dolor crónico en Colombia: Federación Latinoamericana de Asociaciones para el Estudio del Dolor [Internet]. 2014 [cited 2022 Jan 12]. Available from: http://fedelat.com/encuestade-dolor-2/
Casanova-García C, Lerma Lara S, Pérez Ruiz M, Ruano Domínguez D, Santana Sosa E. Non-pharmacological treatment for neuropathic pain in children with cancer. Med Hypotheses. 2015 Dec;85(6):791–7.
Corrêa LA, Bittencourt JV, Mainenti Pagnez MA, Mathieson S, Saragiotto BT, Telles GF, et al. Neural management plus advice to stay active on clinical measures and sciatic neurodynamic for patients with chronic sciatica: Study protocol for a controlled randomised clinical trial. PloS One. 2022;17(2):e0263152.
Zhang Y-H, Hu H-Y, Xiong Y-C, Peng C, Hu L, Kong Y-Z, et al. Exercise for Neuropathic Pain: A Systematic Review and Expert Consensus. Front Med. 2021;8:756940.
Yang S, Chang MC. Effect of Repetitive Transcranial Magnetic Stimulation on Pain Management: A Systematic Narrative Review. Front Neurol. 2020;11:114.
Yu K, Niu X, He B. Neuromodulation Management of Chronic Neuropathic Pain in The Central Nervous system. Adv Funct Mater. 2020 Sep 10;30(37):1908999.
Bernetti A, Agostini F, de Sire A, Mangone M, Tognolo L, Di Cesare A, et al. Neuropathic Pain and Rehabilitation: A Systematic Review of International Guidelines. Diagn Basel Switz. 2021 Jan 5;11(1):74.
Barros Galvão SC, Borba Costa dos Santos R, Borba dos Santos P, Cabral ME, Monte-Silva K. Efficacy of coupling repetitive transcranial magnetic stimulation and physical therapy to reduce upper-limb spasticity in patients with stroke: a randomized controlled trial. Arch Phys Med Rehabil. 2014 Feb;95(2):222–9.
Dos Santos RBC, Galvão SCB, Frederico LMP, Amaral NSL, Carneiro MIS, de Moura Filho AG, et al. Cortical and spinal excitability changes after repetitive transcranial magnetic stimulation combined to physiotherapy in stroke spastic patients. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2019 Jun;40(6):1199–207.
Lefaucheur J-P, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2020 Feb;131(2):474–528.
Gunduz A, Kumru H, Pascual-Leone A. Outcomes in spasticity after repetitive transcranial magnetic and transcranial direct current stimulations. Neural Regen Res. 2014 Apr 1;9(7):712–8.
Mendonca ME, Simis M, Grecco LC, Battistella LR, Baptista AF, Fregni F. Transcranial Direct Current Stimulation Combined with Aerobic Exercise to Optimize Analgesic Responses in Fibromyalgia: A Randomized Placebo-Controlled Clinical Trial. Front Hum Neurosci. 2016;10:68.
Ramger BC, Bader KA, Davies SP, Stewart DA, Ledbetter LS, Simon CB, et al. Effects of Non-Invasive Brain Stimulation on Clinical Pain Intensity and Experimental Pain Sensitivity Among Individuals with Central Post-Stroke Pain: A Systematic Review. J Pain Res. 2019;12:3319–29.
Garcia-Pallero MÁ, Cardona D, Rueda-Ruzafa L, Rodriguez-Arrastia M, Roman P. Central nervous system stimulation therapies in phantom limb pain: a systematic review of clinical trials. Neural Regen Res. 2022 Jan;17(1):59–64.
Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021) [Internet]. Cochrane; 2021. Available from: www.training.cochrane.org/handbook
Urrútia G, Bonfill X. [PRISMA declaration: a proposal to improve the publication of systematic reviews and meta-analyses]. Med Clin (Barc). 2010 Oct 9;135(11):507–11.
Oslo Nor Knowl Cent Health Serv. Cochrane Effective Practice and Organisation of Care Group. Eff Pract Organ Care EPOC Suggest Risk Bias Criteria EPOC Rev EPOC Resour Rev Authors . 2015. 2015.
Jin Y, Xing G, Li G, Wang A, Feng S, Tang Q, et al. High Frequency Repetitive Transcranial Magnetic Stimulation Therapy For Chronic Neuropathic Pain: A Meta-analysis. Pain Physician. 2015 Nov;18(6):E1029-1046.
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011 Oct 18;343:d5928.
National Institute of Heart, lungs and blood (NIHLBI). NIH. Estudiar herramientas de evaluación de la calidad [Internet]. Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
GRADE home [Internet]. GRADE home. [cited 2021 Jan 12]. Available from: http://www.gradeworkinggroup.org/
Aguayo-Albasini JL, Flores-Pastor B, Soria-Aledo V. Sistema GRADE: clasificación de la calidad de la evidencia y graduación de la fuerza de la recomendación. Cir Esp. 2014;92(2):82–8.
Gradepro [Internet]. Gradepro. [cited 2022 Jan 12]. Available from: https://gradepro.org/
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 Apr;19(4):519–27.
Quesada C, Pommier B, Fauchon C, Bradley C, Créac’h C, Murat M, et al. New procedure of high-frequency repetitive transcranial magnetic stimulation for central neuropathic pain: a placebo-controlled randomized crossover study. Pain. 2020 Apr;161(4):718–28.
Abdelkader AA, El Gohary AM, Mourad HS, El Salmawy DA. Repetitive TMS in treatment of resistant diabetic neuropathic pain. Egypt J Neurol Psychiatry Neurosurg. 2019 May 22;55(1):30.
Ahmed GM, Maher EA, Elnassag BAEMR, Sayed HM, Kabbash SI. Effects of repetitive transcranial magnetic stimulation versus transcutaneous electrical nerve stimulation to decrease diabetic neuropathic pain. Int J Ther Rehabil. 2020 Feb 2;27(2):1–10.
Attal N, Ayache SS, Ciampi De Andrade D, Mhalla A, Baudic S, Jazat F, et al. Repetitive transcranial magnetic stimulation and transcranial direct-current stimulation in neuropathic pain due to radiculopathy: a randomized sham-controlled comparative study. Pain. 2016 Jun;157(6):1224–31.
Cervigni M, Onesti E, Ceccanti M, Gori MC, Tartaglia G, Campagna G, et al. Repetitive transcranial magnetic stimulation for chronic neuropathic pain in patients with bladder pain syndrome/interstitial cystitis. Neurourol Urodyn. 2018 Nov;37(8):2678–87.
Hosomi K, Sugiyama K, Nakamura Y, Shimokawa T, Oshino S, Goto Y, et al. A randomized controlled trial of 5 daily sessions and continuous trial of 4 weekly sessions of repetitive transcranial magnetic stimulation for neuropathic pain. Pain. 2020 Feb;161(2):351–60.
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 Jul;154(7):1065–72.
Kim JK, Park HS, Bae JS, Jeong YS, Jung KJ, Lim JY. Effects of multi-session intermittent theta burst stimulation on central neuropathic pain: A randomized controlled trial. NeuroRehabilitation. 2020 Jan 1;46(1):127–34.
Goto Y, Hosomi K, Shimokawa T, Shimizu T, Yoshino K, Kim SJ, et al. Pilot study of repetitive transcranial magnetic stimulation in patients with chemotherapy-induced peripheral neuropathy. J Clin Neurosci Off J Neurosurg Soc Australas. 2020 Mar;73:101–7.
Lindholm P, Lamusuo S, Taiminen T, Pesonen U, Lahti A, Virtanen A, et al. Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation. Pain. 2015 Jul;156(7):1276–83.
Pommier B, Créac’h C, Beauvieux V, Nuti C, Vassal F, Peyron R. Robot-guided neuronavigated rTMS as an alternative therapy for central (neuropathic) pain: Clinical experience and long-term follow-up. Eur J Pain Lond Engl. 2016 Jan 14;20.
Ayache SS, Ahdab R, Chalah MA, Farhat WH, Mylius V, Goujon C, et al. Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain. Eur J Pain Lond Engl. 2016 Oct;20(9):1413–22.
Hodaj H, Payen J-F, Hodaj E, Dumolard A, Maindet C, Cracowski J-L, et al. Long-term treatment of chronic orofacial, pudendal, and central neuropathic limb pain with repetitive transcranial magnetic stimulation of the motor cortex. Clin Neurophysiol. 2020 Jul 1;131(7):1423–32.
Lawson McLean A, Frank S, Zafar N, Waschke A, Kalff R, Reichart R. Time course of the response to navigated repetitive transcranial magnetic stimulation at 10 Hz in chronic neuropathic pain. Neurol Res. 2018 Jul;40(7):564–72.
Lefaucheur J-P, Ayache SS, Sorel M, Farhat WH, Zouari HG, Ciampi de Andrade D, et al. Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming. Eur J Pain Lond Engl. 2012 Nov;16(10):1403–13.
Nurmikko T, MacIver K, Bresnahan R, Hird E, Nelson A, Sacco P. Motor Cortex Reorganization and Repetitive Transcranial Magnetic Stimulation for Pain-A Methodological Study. Neuromodulation J Int Neuromodulation Soc. 2016 Oct;19(7):669–78.
Sampson SM, Kung S, McAlpine DE, Sandroni P. The use of slow-frequency prefrontal repetitive transcranial magnetic stimulation in refractory neuropathic pain. J ECT. 2011 Mar;27(1):33–7.
Jiang X, Yan W, Wan R, Lin Y, Zhu X, Song G, et al. Effects of repetitive transcranial magnetic stimulation on neuropathic pain: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2022 Jan;132:130–41.
Attia M, McCarthy D, Abdelghani M. Repetitive Transcranial Magnetic Stimulation for Treating Chronic Neuropathic Pain: a Systematic Review. Curr Pain Headache Rep. 2021 May 12;25(7):48.
Che X, Cash RFH, Luo X, Luo H, Lu X, Xu F, et al. High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: A systematic review and meta-analysis. Brain Stimulat. 2021 Oct;14(5):1135–46.
Kwon JH. Overcoming barriers in cancer pain management. J Clin Oncol Off J Am Soc Clin Oncol. 2014 Jun 1;32(16):1727–33.
Hall JA, Konstantinou K, Lewis M, Oppong R, Ogollah R, Jowett S. Systematic Review of Decision Analytic Modelling in Economic Evaluations of Low Back Pain and Sciatica. Appl Health Econ Health Policy. 2019 Aug;17(4):467–91.
Piano V. A Case Vignette Study to Assess the Knowledgeof Pain Physicians of Neuropathic Cancer Pain:Room for Improvement. Pain Physician. 2013 Nov 14;6;16(6;11):E779–88.
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 May;154(5):690–9.
Giménez-Campos MS, Pimenta-Fermisson-Ramos P, Díaz-Cambronero JI, Carbonell-Sanchís R, López-Briz E, Ruíz-García V. A systematic review and meta-analysis of the effectiveness and adverse events of gabapentin and pregabalin for sciatica pain. Aten Primaria. 2022 Jan;54(1):102144.
Lopes-Júnior LC, Rosa GS, Pessanha RM, Schuab SIP de C, Nunes KZ, Amorim MHC. Efficacy of the complementary therapies in the management of cancer pain in palliative care: A systematic review. Rev Lat Am Enfermagem. 2020;28:e3377.
Lefaucheur J-P, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov 1;125(11):2150–206.

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Reviewers agreed at journal
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Effectiveness of transcranial magnetic stimulation in the management of oncological and non-oncological neuropathic pain. A systematic review

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Abstract

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Introduction

Methodology

Selection criteria

Types of participants

Type of Intervention

Settings

Comparison

Outcome measures

Exclusion criteria

Search Methods

Data collection and analysis

Selection of studies

Data extraction

Assessment of the risk of bias

Data Synthesis

Quality of evidence

Results

Discussion

Conclusion

Declarations

References

Supplementary Files

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