A randomized controlled trial of 5 daily sessions and continuous trial of 4 weekly sessions of repetitive transcranial magnetic stimulation for neuropathic pain

Koichi Hosomi, Kenji Sugiyama, Yusaku Nakamura, Toshio Shimokawa, Satoru Oshino, Yuko Goto, Tomoo Mano, Takeshi Shimizu, Takufumi Yanagisawa, Youichi Saitoh, TEN-P11-01 investigators, Koichi Hosomi, Kenji Sugiyama, Yusaku Nakamura, Toshio Shimokawa, Satoru Oshino, Yuko Goto, Tomoo Mano, Takeshi Shimizu, Takufumi Yanagisawa, Youichi Saitoh, TEN-P11-01 investigators

Abstract

We conducted a multicenter, randomized, patient- and assessor-blinded, sham-controlled trial to investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in patients with neuropathic pain (NP). Patients were randomly assigned to receive 5 daily sessions of active or sham rTMS of M1 corresponding to the part of the body experiencing the worst pain (500 pulses per session at 5 Hz). Responders were invited to enroll in an open-label continuous trial involving 4 weekly sessions of active rTMS. The primary outcome was a mean decrease in a visual analogue scale of pain intensity (scaled 0-100 mm) measured daily during the daily sessions in an intention-to-treat population. Secondary outcomes were other pain scores, quality-of-life measures, and depression score. One hundred forty-four patients were assigned to the active or sham stimulation groups. The primary outcome, mean visual analogue scale decreases, was not significantly different (P = 0.58) between the active stimulation group (mean, 8.0) and the sham group (9.2) during the daily sessions. The secondary outcomes were not significantly different between 2 groups. The patients enrolled in the continuous weekly rTMS achieved more pain relief in the active stimulation group compared with the sham (P < 0.01). No serious adverse events were observed. Five daily sessions of rTMS with stimulus conditions used in this trial were ineffective in short-term pain relief in the whole study population with various NP. Long-term administration to the responders should be investigated for the clinical use of rTMS on NP in the future trials.

Conflict of interest statement

K. Hosomi, K. Sugiyama, Y. Nakamura, T. Shimokawa, and Y. Saitoh had grants from AMED during the conduct of the study. Y. Saitoh received consultancy fees from Teijin Pharma Limited during the conduct of the study. Y. Saitoh has an issued patent about TMS coils. K. Hosomi, Y. Goto, T. Mano, T. Shimizu, and Y. Saitoh belong to the Department of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine, which is a joint research department established with sponsorship by Teijin Pharma Limited. The remaining authors have no conflicts of interest to declare.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Trial schedule. D, day; rTMS, repetitive transcranial magnetic stimulation; W, week.
Figure 2.
Figure 2.
Image of the rTMS equipment. rTMS, repetitive transcranial magnetic stimulation.
Figure 3.
Figure 3.
Flow diagram. GCP, good clinical practice; rTMS, repetitive transcranial magnetic stimulation.
Figure 4.
Figure 4.
Time course of pain scores during the evaluation period in the intention-to-treat population. The mean and 95% CI are shown for (A) visual analogue scale (VAS) and (B) short-form McGill pain questionnaire 2 (SF-MPQ2) at baseline, that is, before the 1st-day intervention, and after each intervention in the evaluation period. CI, confidence interval; D, day.
Figure 5.
Figure 5.
Time course of pain scores in patients enrolled in the continuous trial. The means and 95% CI are shown for (A) visual analogue scale (VAS) and (B) short-form McGill pain questionnaire 2 (SF-MPQ2) at baseline, after each intervention and at the last follow-up. Significant changes from the baseline are indicated as *P < 0.05; **P < 0.01; ***P < 0.001. CI, confidence interval; D, day; W, week.

References

    1. Andre-Obadia N, Magnin M, Simon E, Garcia-Larrea L. Somatotopic effects of rTMS in neuropathic pain? A comparison between stimulation over hand and face motor areas. Eur J Pain 2018;22:707–15.
    1. Attal N, Ayache SS, Ciampi De Andrade D, Mhalla A, Baudic S, Jazat F, Ahdab R, Neves DO, Sorel M, Lefaucheur JP, Bouhassira D. Repetitive transcranial magnetic stimulation and transcranial direct-current stimulation in neuropathic pain due to radiculopathy: a randomized sham-controlled comparative study. PAIN 2016;157:1224–31.
    1. Ayache SS, Ahdab R, Chalah MA, Farhat WH, Mylius V, Goujon C, Sorel M, Lefaucheur JP. Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain. Eur J Pain 2016;20:1413–22.
    1. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010;9:807–19.
    1. Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, Simpson BA, Taylor RS. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 2007;14:952–70.
    1. Cruccu G, Garcia-Larrea L, Hansson P, Keindl M, Lefaucheur JP, Paulus W, Taylor R, Tronnier V, Truini A, Attal N. EAN guidelines on central neurostimulation therapy in chronic pain conditions. Eur J Neurol 2016;23:1489–99.
    1. Dworkin RH, O'Connor AB, Kent J, Mackey SC, Raja SN, Stacey BR, Levy RM, Backonja M, Baron R, Harke H, Loeser JD, Treede RD, Turk DC, Wells CD. Interventional management of neuropathic pain: NeuPSIG recommendations. PAIN 2013;154:2249–61.
    1. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Revicki DA, Rothman M, Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE, Witter J, Zavisic S. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9:105–21.
    1. European Medicines Agency. Guideline on the clinical development of medicinal products intended for the treatment of pain. London, United Kingdom: European Medicines Agency, 2016.
    1. EuroQol G. EuroQol—a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
    1. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa 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;14:162–73.
    1. Hamada M, Ugawa Y, Tsuji S. High-frequency rTMS over the supplementary motor area for treatment of Parkinson's disease. Mov Disord 2008;23:1524–31.
    1. Hanajima R, Wang R, Nakatani-Enomoto S, Hamada M, Terao Y, Furubayashi T, Okabe S, Inomata-Terada S, Yugeta A, Rothwell JC, Ugawa Y. Comparison of different methods for estimating motor threshold with transcranial magnetic stimulation. Clin Neurophysiol 2007;118:2120–2.
    1. Hirayama A, Saitoh Y, Kishima H, Shimokawa T, Oshino S, Hirata M, Kato A, Yoshimine T. Reduction of intractable deafferentation pain by navigation-guided repetitive transcranial magnetic stimulation of the primary motor cortex. PAIN 2006;122:22–7.
    1. Hosomi K, Seymour B, Saitoh Y. Modulating the pain network—neurostimulation for central poststroke pain. Nat Rev Neurol 2015;11:290–9.
    1. Hosomi K, Shimokawa T, Ikoma K, Nakamura Y, Sugiyama K, Ugawa Y, Uozumi T, Yamamoto T, Saitoh Y. Daily repetitive transcranial magnetic stimulation of primary motor cortex for neuropathic pain: a randomized, multicenter, double-blind, crossover, sham-controlled trial. PAIN 2013;154:1065–72.
    1. Khedr EM, Kotb HI, Mostafa MG, Mohamad MF, Amr SA, Ahmed MA, Karim AA, Kamal SM. Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: a randomized clinical trial. Eur J Pain 2015;19:519–27.
    1. Klein MM, Treister R, Raij T, Pascual-Leone A, Park L, Nurmikko T, Lenz F, Lefaucheur JP, Lang M, Hallett M, Fox M, Cudkowicz M, Costello A, Carr DB, Ayache SS, Oaklander AL. Transcranial magnetic stimulation of the brain: guidelines for pain treatment research. PAIN 2015;156:1601–14.
    1. Kobayashi M, Fujimaki T, Mihara B, Ohira T. Repetitive transcranial magnetic stimulation once a week induces sustainable long-term relief of central poststroke pain. Neuromodulation 2015;18:249–54.
    1. Lefaucheur JP. The use of repetitive transcranial magnetic stimulation (rTMS) in chronic neuropathic pain. Neurophysiol Clin 2006;36:117–24.
    1. Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014;125:2150–206.
    1. Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol 2017;128:56–92.
    1. Lefaucheur JP, Hatem S, Nineb A, Menard-Lefaucheur I, Wendling S, Keravel Y, Nguyen JP. Somatotopic organization of the analgesic effects of motor cortex rTMS in neuropathic pain. Neurology 2006;67:1998–2004.
    1. Lenz M, Vlachos A. Releasing the cortical brake by non-invasive electromagnetic stimulation? rTMS induces LTD of GABAergic neurotransmission. Front Neural Circuits 2016;10:96.
    1. Leung A, Donohue M, Xu R, Lee R, Lefaucheur JP, Khedr EM, Saitoh Y, Andre-Obadia N, Rollnik J, Wallace M, Chen R. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain 2009;10:1205–16.
    1. Lima MC, Fregni F. Motor cortex stimulation for chronic pain: systematic review and meta-analysis of the literature. Neurology 2008;70:2329–37.
    1. Loeser JD, Treede RD. The kyoto protocol of IASP basic pain terminology. PAIN 2008;137:473–7.
    1. Maruo T, Nakae A, Maeda L, Shi K, Takahashi K, Morris S, Hosomi K, Kanatani H, Matsuzaki T, Saitoh Y. Validity, reliability, and assessment sensitivity of the Japanese version of the short-form McGill pain questionnaire 2 in Japanese patients with neuropathic and non-neuropathic pain. Pain Med 2014;15:1930–7.
    1. 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 2016;19:669–78.
    1. O'Connell NE, Marston L, Spencer S, DeSouza LH, Wand BM. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev 2018;4:CD008208.
    1. Pommier B, Creac'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 2016;20:907–16.
    1. Quesada C, Pommier B, Fauchon C, Bradley C, Creac'h C, Vassal F, Peyron R. Robot-Guided neuronavigated repetitive transcranial magnetic stimulation (rTMS) in central neuropathic pain. Arch Phys Med Rehabil 2018;99:2203.e2201–15.e2201.
    1. Quesada C, Pommier B, Fauchon C, Créaćh C, Vassal F, Peyron R. Neuronavigated 20 Hz rTMS efficiency in patients with central pain. A placebo controlled randomized cross-over study. Proceedings, 17th World Congress on Pain, Boston, September 14, 2018.
    1. Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120:2008–39.
    1. Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application: an updated report from an I.F.C.N. Committee. Clin Neurophysiol 2015;126:1071–107.
    1. Saitoh Y, Hirayama A, Kishima H, Shimokawa T, Oshino S, Hirata M, Tani N, Kato A, Yoshimine T. Reduction of intractable deafferentation pain due to spinal cord or peripheral lesion by high-frequency repetitive transcranial magnetic stimulation of the primary motor cortex. J Neurosurg 2007;107:555–9.
    1. Sekino M, Ohsaki H, Takiyama Y, Yamamoto K, Matsuzaki T, Yasumuro Y, Nishikawa A, Maruo T, Hosomi K, Saitoh Y. Eccentric figure-eight coils for transcranial magnetic stimulation. Bioelectromagnetics 2015;36:55–65.
    1. Shimizu T, Hosomi K, Maruo T, Goto Y, Yokoe M, Kageyama Y, Shimokawa T, Yoshimine T, Saitoh Y. Efficacy of deep rTMS for neuropathic pain in the lower limb: a randomized, double-blind crossover trial of an H-coil and figure-8 coil. J Neurosurg 2017;127:1172–80.
    1. Wager TD, Fields HL. Placebo analgesia. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC, editors. Wall and Melzack's textbook of pain. Philadelphia: Elsevier Saunders, 2013. pp. 362–73.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera