Brazilian Journal of Pain
https://brjp.org.br/article/doi/10.63231/2595-0118.202660-en
Brazilian Journal of Pain
Review Article

Intermittent theta burst stimulation in the treatment of neuropathic pain: systematic review and meta-analysis

Estimulação theta burst intermitente no tratamento da dor neuropática: revisão sistemática e meta-análise

Flávio Antônio Duboc Flutt; Lucas Machado da Rocha Tarlé; Rayssa Paula Paz Furlanetto; Nivaldo Ribeiro Villela

http://dx.doi.org/10.63231/2595-0118.202660-en BrJP, vol.9, e202660, 2026
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Abstract

BACKGROUND AND OBJECTIVES: Intermittent theta burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS), is an established treatment for depression, but its role in neuropathic pain remains unclear. The objective of this study was to conduct a systematic review and meta-analysis to evaluate the effect of iTBS on neuropathic pain.

CONTENTS: The review followed the Cochrane Handbook and PRISMA guidelines (PROSPERO ID: CRD42024584969). Eligible randomized controlled trials in Portuguese, English, and Spanish were identified through searches in Pubmed, EMBASE, BVS, and Web of Science. The primary outcome was the change in pain intensity measured by the 11-point Numerical Rating Scale (NRS), considering a reduction of ≥2 points as clinically significant. Mean differences in NRS scores between baseline and post-intervention were analyzed. Subgroups were formed based on the type of control (sham or high-frequency rTMS), and a random-effects meta-analysis was performed. Of 1,062 records screened, four studies met the inclusion criteria. Two trials using sham controls demonstrated significant pain reduction with iTBS, while three comparing iTBS with rTMS favored rTMS. Substantial heterogeneity was observed (I2 = 51% for sham and 53% for rTMS comparisons). No major adverse effects were reported.

CONCLUSION: Preliminary evidence suggests that iTBS may be an effective and time-efficient neuromodulatory approach for neuropathic pain, though results are inconsistent when compared to rTMS. Larger, multicenter randomized trials are required to confirm efficacy and clarify optimal stimulation protocols.

Supplementary material

Keywords

Neuralgia; Pain; Systematic review; Transcranial magnetic stimulation

Resumo

JUSTIFICATIVA E OBJETIVOS: A estimulação theta burst intermitente (iTBS), uma forma padronizada de estimulação magnética transcraniana repetitiva (rTMS), é um tratamento estabelecido para depressão, mas seu papel na dor neuropática ainda não está bem definido. O objetivo deste estudo foi realizar uma revisão sistemática e meta-análise para avaliar o efeito da iTBS na dor neuropática.

CONTEÚDO: O estudo seguiu as recomendações do Cochrane Handbook e as diretrizes PRISMA (PROSPERO ID: CRD42024584969). Ensaios clínicos randomizados em português, inglês e espanhol foram identificados nas bases Pubmed, EMBASE, BVS e Web of Science. O desfecho primário foi a variação da intensidade da dor medida pela Escala Numérica de 11 pontos (NRS), considerando-se clinicamente significativa uma redução = 2 pontos. As diferenças médias entre o pré e o pós-intervenção foram analisadas, e as comparações foram divididas conforme o tipo de controle (sham ou rTMS de alta frequência). Foi realizada uma meta-análise com modelo de efeitos aleatórios. De 1.062 registros identificados, quatro estudos preencheram os critérios de inclusão. Dois ensaios com controle sham mostraram redução significativa da dor com iTBS, enquanto três comparando iTBS e rTMS favoreceram o rTMS. Observou-se heterogeneidade substancial (I2 = 51% para o grupo sham e 53% para o grupo rTMS). Nenhum efeito adverso relevante foi relatado.

CONCLUSÃO: As evidências preliminares sugerem que a iTBS pode ser uma abordagem neuromodulatória eficaz e de curta duração para o tratamento da dor neuropática. No entanto, são necessários ensaios multicêntricos e de maior escala para confirmar sua eficácia e definir protocolos ideais de estimulação.

Material suplementar

Palavras-chave

Dor; Estimulação magnética transcraniana; Neuralgia; Revisão sistemática

References

1 Scholz J, Finnerup NB, Attal N, Aziz Q, Baron R, Bennett MI, Benoliel R, Cohen M, Cruccu G, Davis KD, Evers S, First M, Giamberardino MA, Hansson P, Kaasa S, Korwisi B, Kosek E, Lavand’homme P, Nicholas M, Nurmikko T, Perrot S, Raja SN, Rice ASC, Rowbotham MC, Schug S, Simpson DM, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ, Barke A, Rief W, Treede RD, Classification Committee of the Neuropathic Pain Special Interest Group (NeuPSIG). The IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain. 2019;160(1):53-9. https://doi.org/10.1097/j.pain.0000000000001365. PMid:30586071.

2 Bouhassira D, Attal N. Personalized treatment of neuropathic pain: where are we now? Eur J Pain. 2023;27(9):1084-98. https://doi.org/10.1002/ejp.2120. PMid:37114461.

3 van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014;155(4):654-62. https://doi.org/10.1016/j.pain.2013.11.013. PMid:24291734.

4 Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380-7. https://doi.org/10.1016/j.pain.2007.08.013. PMid:17888574.

5 Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-73. https://doi.org/10.1016/S1474-4422(14)70251-0. PMid:25575710.

6 Attal N, Bouhassira D, Colvin L. Advances and challenges in neuropathic pain: a narrative review and future directions. Br J Anaesth. 2023;131(1):79-92. https://doi.org/10.1016/j.bja.2023.04.021. PMid:37210279.

7 Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipović SR, Grefkes C, Hasan A, Hummel FC, Jääskeläinen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorová I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018). Clin Neurophysiol. 2020;131(2):474-528. https://doi.org/10.1016/j.clinph.2019.11.002. PMid:31901449.

8 Ge SY, Hu MM, Li KP, Wu CQ, Xu GH, Dong L. Comparative efficacy of common rehabilitation treatments for patients with neuropathic pain after spinal cord injury: a systematic review and network meta-analysis. Neurol Sci. 2025;46(8):3547-57. https://doi.org/10.1007/s10072-025-08120-y. PMid:40167861.

9 Galhardoni R, Correia GS, Araujo H, Yeng LT, Fernandes DT, Kaziyama HH, Marcolin MA, Bouhassira D, Teixeira MJ, de Andrade DC. Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. Arch Phys Med Rehabil. 2015;96(4, Suppl):S156-72. https://doi.org/10.1016/j.apmr.2014.11.010. PMid:25437106.

10 Moisset X, De Andrade DC, Bouhassira D. From pulses to pain relief: an update on the mechanisms of rTMS-induced analgesic effects. Eur J Pain. 2016;20(5):689-700. https://doi.org/10.1002/ejp.811. PMid:26471248.

11 Pell GS, Roth Y, Zangen A. Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms. Prog Neurobiol. 2011;93(1):59-98. https://doi.org/10.1016/j.pneurobio.2010.10.003. PMid:21056619.

12 Valero-Cabré A, Amengual JL, Stengel C, Pascual-Leone A, Coubard OA. Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights. Neurosci Biobehav Rev. 2017;83:381-404. https://doi.org/10.1016/j.neubiorev.2017.10.006. PMid:29032089.

13 Hussain SJ, Freedberg MV. Debunking the myth of excitatory and inhibitory repetitive transcranial magnetic stimulation in cognitive neuroscience research. J Cogn Neurosci. 2025;37(5):1009-22. https://doi.org/10.1162/jocn_a_02288. PMid:39785679.

14 Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201-6. https://doi.org/10.1016/j.neuron.2004.12.033. PMid:15664172.

15 Di Lazzaro V, Pilato F, Dileone M, Profice P, Oliviero A, Mazzone P, Insola A, Ranieri F, Meglio M, Tonali PA, Rothwell JC. The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol. 2008;586(16):3871-9. https://doi.org/10.1113/jphysiol.2008.152736. PMid:18566003.

16 Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391(10131):1683-92. https://doi.org/10.1016/S0140-6736(18)30295-2. PMid:29726344.

17 Fernandes AM, Graven-Nielsen T, De Andrade DC. New updates on transcranial magnetic stimulation in chronic pain. Curr Opin Support Palliat Care. 2022;16(2):65-70. https://doi.org/10.1097/SPC.0000000000000591. PMid:35639571.

18 Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: a new form of TMS treatment for depression? Depress Anxiety. 2015;32(3):182-92. https://doi.org/10.1002/da.22335. PMid:25450537.

19 Kishi T, Ikuta T, Sakuma K, Hatano M, Matsuda Y, Wilkening J, Goya-Maldonado R, Tik M, Williams NR, Kito S, Iwata N. Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis. Mol Psychiatry. 2024;29(12):3893-9. https://doi.org/10.1038/s41380-024-02630-5. PMid:38844532.

20 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:372. PMid:33782057.

21 Farrar JT, Young JP Jr, 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(2):149-58. https://doi.org/10.1016/S0304-3959(01)00349-9. PMid:11690728.

22 Yang C, Bi Y, Hu L, Gong L, Li Z, Zhang N, Wang Q, Li J. Effects of different transcranial magnetic stimulations on neuropathic pain after spinal cord injury. Front Neurol. 2023;14:1141973. https://doi.org/10.3389/fneur.2023.1141973. PMid:37521294.

23 Kim JK, You JI, Son S, Suh IH, Lim JY. Comparison of intermittent theta burst stimulation and high-frequency repetitive transcranial magnetic stimulation on spinal cord injury-related neuropathic pain: a sham-controlled study. J Spinal Cord Med. 2025;48(2):241-7. https://doi.org/10.1080/10790268.2023.2277964. PMid:37982995.

24 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;46(1):127-34. https://doi.org/10.3233/NRE-192958. PMid:32039876.

25 André-Obadia N, Magnin M, Garcia-Larrea L. Theta-burst versus 20 Hz repetitive transcranial magnetic stimulation in neuropathic pain: a head-to-head comparison. Clin Neurophysiol. 2021;132(10):2702-10. https://doi.org/10.1016/j.clinph.2021.05.022. PMid:34217600.

26 Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad BSR, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry. 2022;179(2):132-41. https://doi.org/10.1176/appi.ajp.2021.20101429. PMid:34711062.

27 Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, Nejad R, Pankow H, Choi E, Aaron H, Espil FM, Pannu J, Xiao X, Duvio D, Solvason HB, Hawkins J, Guerra A, Jo B, Raj KS, Phillips AL, Barmak F, Bishop JH, Coetzee JP, DeBattista C, Keller J, Schatzberg AF, Sudheimer KD, Williams NR. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-26. https://doi.org/10.1176/appi.ajp.2019.19070720. PMid:32252538.

28 Hutton TM, Aaronson ST, Carpenter LL, Pages K, Krantz D, Lucas L, Chen B, Sackeim HA. Dosing transcranial magnetic stimulation in major depressive disorder: relations between number of treatment sessions and effectiveness in a large patient registry. Brain Stimul. 2023;16(5):1510-21. https://doi.org/10.1016/j.brs.2023.10.001. PMid:37827360.

29 Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9(3):336-46. https://doi.org/10.1016/j.brs.2016.03.010. PMid:27090022.

30 Brunoni AR, Sampaio-Junior B, Moffa AH, Aparicio LV, Gordon P, Klein I, Rios RM, Razza LB, Loo C, Padberg F, Valiengo L. Noninvasive brain stimulation in psychiatric disorders: a primer. Br J Psychiatry. 2019;41(1):70-81. https://doi.org/10.1590/1516-4446-2017-0018. PMid:30328957.

31 Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmöller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M, basis of this article began with a Consensus Statement from the IFCN Workshop on “Present, Future of TMS: Safety, Ethical Guidelines”, Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines. Clin Neurophysiol. 2021;132(1):269-306. https://doi.org/10.1016/j.clinph.2020.10.003. PMid:33243615.

32 Ferrulli A, Massarini S, Macrì C, Luzi L. Safety and tolerability of repeated sessions of deep transcranial magnetic stimulation in obesity. Endocrine. 2021;71(2):331-43. https://doi.org/10.1007/s12020-020-02496-x. PMid:32964308.

33 Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain. 2015;156(Suppl 1):S24-31. https://doi.org/10.1097/01.j.pain.0000460343.46847.58. PMid:25789433.

34 Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010;23(5):611-5. https://doi.org/10.1097/ACO.0b013e32833c348b. PMid:20543676.

35 Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895-926. https://doi.org/10.1016/j.jpain.2009.06.012. PMid:19712899.

36 Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3, Suppl):S2-15. https://doi.org/10.1016/j.pain.2010.09.030. PMid:20961685.

37 von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73(4):638-52. https://doi.org/10.1016/j.neuron.2012.02.008. PMid:22365541.

38 De Deng Z, Peterchev AV, Lisanby SH. Coil design considerations for deep-brain transcranial magnetic stimulation (dTMS). Annu Int Conf IEEE Eng Med Biol Soc. 2008;2008:5675-9. https://doi.org/10.1109/IEMBS.2008.4650502. PMid:19164005.

39 Garcia-Larrea L, Peyron R. Pain matrices and neuropathic pain matrices: a review. Pain. 2013;154(Suppl 1):154. https://doi.org/10.1016/j.pain.2013.09.001. PMid:24021862.

40 Geyer S, Schleicher A, Zilles K. Areas 3a, 3b, and 1 of human primary somatosensory cortex: 1. Microstructural organization and interindividual variability. Neuroimage. 1999;10(1):63-83. https://doi.org/10.1006/nimg.1999.0440. PMid:10385582.

41 Lefaucheur JP, Ayache SS, Sorel M, Farhat WH, Zouari HG, Ciampi De Andrade D, Ahdab R, Ménard-Lefaucheur I, Brugières P, Goujon C. Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming. Eur J Pain. 2012;16(10):1403-13. https://doi.org/10.1002/j.1532-2149.2012.00150.x. PMid:22508405.
 

Submitted date:
11/02/2025

Accepted date:
01/12/2026

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